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Introduction: CD39 plays an important role in the immunoregulation and inhibition of effector cells. It is expressed on immune cells, including Tregs, and on extracellular vesicles (EVs) budding from the plasma membrane. Platelet transfusion may induce alloimmunization against HLA-I antigens, leading to refractoriness to platelet transfusion with severe consequences for patients. Tregs may play a key role in determining whether alloimmunization occurs in patients with hematologic disorders. We hypothesized that CD39 + EVs might play an immunoregulatory role, particularly in the context of platelet transfusions in patients with hematologic disorders. Such alloimmunization leads to the production of alloantibodies and is sensitive to the regulatory action of CD39., Methods: We characterized CD39 + EVs in platelet concentrates by flow cytometry. The absolute numbers and cellular origins of CD39 + EVs were evaluated. We also performed functional tests to evaluate interactions with immune cells and their functions., Results: We found that CD39 + EVs from platelet concentrates had an inhibitory phenotype that could be transferred to the immune cells with which they interacted: CD4 + and CD8 + T lymphocytes (TLs), dendritic cells, monocytes, and B lymphocytes (BLs). Moreover, the concentration of CD39 + EVs in platelet concentrates varied and was very high in 10% of concentrates. The number of these EVs present was determinant for EV-cell interactions. Finally, functional interactions were observed with BLs, CD4 + TLs and CD39 + EVs for immunoglobulin production and lymphoproliferation, with potential implications for the immunological management of patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Delorme, Laguide, Tamagne, Pinheiro, Cagnet, Neyrinck-Leglantier, Khelfa, Cleophax, Pirenne and Vingert.)

Introduction: People living with HIV (PLWH) now benefit from combined antiviral treatments that durably control viral replication. These antiretroviral treatments decrease mortality and improve quality of life in PLWH, but do not completely control the excessive non-specific activation of the immune system in PLWH. This chronic immune activation is a key element of HIV immunopathology that contributes to the pathophysiology of inflammatory comorbid conditions, such as cardiovascular disorders, cancer and autoimmune diseases. Circulating non-exosomal extracellular vesicles, also known as microparticles (MPs) are detected in these diseases and have been linked to immune activation. The objective of this study was to characterize the MPs present in PLWH and to assess their association with chronic immune activation., Methods: We performed flow cytometry for the complete phenotypic characterization of MPs from fresh plasma from PLWH and from people without HIV as the control group. The absolute number, size and cellular origin of MPs were evaluated. The immunoregulatory profile was determined by cell origin, for MPs derived from platelets (PMPs), monocytes (MMPs) and T lymphocytes (LMPs)., Results: PLWH had significantly more circulating MPs than controls, for MPs of all sizes originating from T lymphocytes, red blood cells, neutrophils, dendritic cells, B lymphocytes and endothelial cells. PMPs and MMPs were not more numerous in PLWH, but the immunoregulatory phenotypes of these MPs differed between PLWH and controls. These differences in immunoregulatory molecule expression profile were also observed for LMPs. PDL1, ICOSL, CCR5, TGFβ1, MHC classes I and II, TRAIL, CXCR4, OX40, DC-SIGN, CTLA4 and PDL2 were more strongly expressed on the surface of MPs from PLWH than on those from controls., Conclusion: MPs are an important element in intercellular communication, making it possible to transfer phenotypes and functions to immune cells. The significantly higher numbers of MPs expressing diverse immunomodulatory molecules in PLWH may make a major contribution to the maintenance and/or the development of immune-cell activation in these individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Neyrinck-Leglantier, Tamagne, Ben Rayana, Many, Vingert, LeGagneux, Delorme, Andrieu, Boilard, Cognasse, Hamzeh-Cognasse, Perez-Patrigeon, Lelievre, Pirenne, Gallien and Vingert.)

Introduction: Acute myeloid leukemia (AML) is one of the commonest hematologic disorders. Due to the high frequency of disease- or treatment-related thrombocytopenia, AML requires treatment with multiple platelet transfusions, which can trigger a humoral response directed against platelets. Some, but not all, AML patients develop an anti-HLA immune response after multiple transfusions. We therefore hypothesized that different immune activation profiles might be associated with anti-HLA alloimmunization status., Methods: We tested this hypothesis, by analyzing CD4+ T lymphocyte (TL) subsets and their immune control molecules in flow cytometry and single-cell multi-omics., Results: A comparison of immunological status between anti-HLA alloimmunized and non-alloimmunized AML patients identified differences in the phenotype and function of CD4+ TLs. CD4+ TLs from alloimmunized patients displayed features of immune activation, with higher levels of CD40 and OX40 than the cells of healthy donors. However, the most notable differences were observed in non-alloimmunized patients. These patients had lower levels of CD40 and OX40 than alloimmunized patients and higher levels of PD1. Moreover, the Treg compartment of non-alloimmunized patients was larger and more functional than that in alloimmunized patients. These results were supported by a multi-omics analysis of immune response molecules in conventional CD4+ TLs, Tfh circulating cells, and Tregs., Discussion: Our results thus reveal divergent CD4+ TL characteristics correlated with anti-HLA alloimmunization status in transfused AML patients. These differences, characterizing CD4+ TLs independently of any specific antigen, should be taken into account when considering the immune responses of patients to infections, vaccinations, or transplantations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Khelfa, Leclerc, Kerbrat, Boudjemai, Benchouaia, Neyrinck-Leglantier, Cagnet, Berradhia, Tamagne, Croisille, Pirenne, Maury and Vingert.)

Introduction: Aplasia and hematological malignancies are treated with platelet transfusions, which can have major immunomodulatory effects. Platelet concentrates (PCs) contain many immunomodulatory elements, including the platelets themselves, residual leukocytes, extracellular vesicles, such as microparticles (MPs), cytokines and other soluble elements. Two of these components, MPs and a soluble form of CD27 (sCD27), have been shown to play a particularly important role in immune system modulation. The loss of CD27 expression is an irreversible marker of terminal effector CD3 + T-lymphocyte (TL) differentiation, and the CD27 + MPs present in PCs may maintain CD27 expression on the surface of TLs, and, thus, the activation of these cells., Methods: In this study, we phenotyped the CD27-expressing MPs present in PCs by microscale flow cytometry and investigated the interaction of these particles with CD4 + TLs. We cocultured MPs and PBMCs and determined the origin of the CD27 expressed on the surface of CD4 + TLs with the aid of two fluorochromes (BV510 for CD27 originating from MPs and BV786 for cellular CD27)., Results: We showed that the binding of CD27- expressing MPs involved the CD70 molecule, which was also present on these MPs. Finally, the maintenance of CD27 expression on the surface of TLs by sorted CD27 + MPs led to activation levels lower than those observed with other types of MPs., Discussion: These results for CD27-expressing MPs and their CD70-mediated targeting open up new possibilities for immunotherapy based on the use of MPs to maintain a phenotype or to target immune cells, for example. Moreover, decreasing the levels of CD27-expressing MPs in transfused platelets might also increase the chances of success for anti-CD27 monoclonal immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cagnet, Neyrinck-Leglantier, Tamagne, Berradhia, Khelfa, Cleophax, Pirenne and Vingert.)

Extracellular vesicles (EVs), which are generated by cell membrane budding in diverse cells, are present in variable numbers in the blood. An immunoregulatory role has been demonstrated principally for heterologous EVs, but the function of the EVs present naturally in blood remains unknown. We hypothesize that these autologous EVs might also modulate the phenotype and function of immune system cells, especially CD4 + T lymphocytes (TLs), as previously described for heterologous EVs. Several membranes and soluble immunoregulatory molecules were studied after the treatment of CD4 + TLs with autologous EVs. No direct activation was detected with autologous EVs, contrasting with the findings for heterologous EVs. However, following treatment with autologous EVs, a soluble form of CD27 (sCD27) was detected. sCD27 is strongly associated with lymphoproliferation. Autologous EVs have been shown to increase TL proliferation only after T-cell receptor (TcR) engagement due to polyclonal or specific-antigen stimulation. Our results therefore suggest that the EVs present in the blood have an immunomodulatory role different from that of heterologous EVs. These findings should be taken into account in future studies, particularly those focusing on infectious diseases, autotransfusion or doping practices., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Neyrinck-Leglantier, Tamagne, L’honoré, Cagnet, Pakdaman, Marchand, Pirenne and Vingert.)

In addition to their hemostatic role, platelets play a significant role in immunity. Once activated, platelets release extracellular vesicles (EVs) formed by the budding of their cytoplasmic membranes. Because of their heterogeneity, platelet EVs (PEVs) are thought to perform diverse functions. It is unknown, however, whether the proteasome is transferred from platelets to PEVs or whether its function is retained. We hypothesized that functional protein processing and antigen presentation machinery are transferred to PEVs by activated platelets. Using molecular and functional assays, we found that the active 20S proteasome was enriched in PEVs, along with major histocompatibility complex class I (MHC-I) and lymphocyte costimulatory molecules (CD40L and OX40L). Proteasome-containing PEVs were identified in healthy donor blood, but did not increase in platelet concentrates that caused adverse transfusion reactions. They were augmented, however, after immune complex injections in mice. The complete biodistribution of murine PEVs after injection into mice revealed that they principally reached lymphoid organs, such as spleen and lymph nodes, in addition to the bone marrow, and to a lesser extent, liver and lungs. The PEV proteasome processed exogenous ovalbumin (OVA) and loaded its antigenic peptide onto MHC-I molecules, which promoted OVA-specific CD8+ T-lymphocyte proliferation. These results suggest that PEVs contribute to adaptive immunity through cross-presentation of antigens and have privileged access to immune cells through the lymphatic system, a tissue location that is inaccessible to platelets., (© 2021 by The American Society of Hematology.)

Background: Platelet (PLT) transfusions are an essential treatment for bleeding disorders. However, immunologic complications can occur, including alloantibody production against Class I HLA molecules. The principal source of HLA molecules in PLT concentrates (PCs) is the PLTs themselves. However, extracellular microparticles (MPs) present in PCs may express HLA molecules., Study Design and Methods: We used nanoscale flow cytometry to explore the expression of HLA-A2, HLA-B7, and HLA-B57 on the surface of cells, PLT-derived MPs (PMPs), lymphocyte-derived MPs (LMPs), and monocyte-derived MPs (MMPs) present in PCs. Expression was studied during 7 days of storage., Results: Platelets were not the only source of HLA molecules in PCs. HLA molecules were present on PMPs, LMPs, and MMPs. The level of HLA Class I molecule expression varied between haplotypes and MPs of different origins and during storage., Conclusion: Platelets or residual cells remaining after leukoreduction are not the only source of HLA Class I molecules in PCs, highlighting the contribution of MPs to alloimmunization mechanisms. These data may be relevant for the development of new transfusion guidelines., (© 2020 AABB.)

It is essential to limit hemolytic transfusion reactions in polytransfused individuals, and the prevention of alloimmunization is a key solution. CD4+ T lymphocyte (TL) markers, particularly follicular T helper (Tfh) cells, may differentiate between responder and nonresponder alloimmunization statuses. We tested this hypothesis by studying the phenotype of CXCR5+PD1+ TLs in whole blood. Our results suggest that high levels of CXCR5+PD1+CD4+ TLs in whole blood may be a characteristic of nonalloimmunized patients. However, these cells did not display the phenotypic characteristics of active Tfh cells. Instead, a decrease in blood quiescent Tfh-cell levels was observed in nonalloimmunized polytransfused patients. High levels of CXCR5+PD1+CD4+ TLs may be associated with inhibitory signaling functions of T cells, as reflected by the low levels of PD1+ICOS+ cells in the nonalloimmunized polytransfused group. The description of these particular phenotypes, and their comparison among groups of patients, responders, and nonresponders, suggests that new immunological components should be considered when trying to understand posttransfusion alloimmunization., (© 2021 by The American Society of Hematology.)

Background: Patients with hematologic malignancies require prophylactic or curative platelet transfusions to prevent or treat bleeding. Treatments such as chemotherapy, radiotherapy, and hematopoietic stem cell transplantation cause persistent thrombocytopenia, necessitating platelet transfusions. However, class I HLA antibodies can cause a serious complication: immune-mediated platelet refractoriness. The mechanisms of alloimmunization are incompletely understood. We explored the immunogenicity of HLA molecules and the phenotype of the HLA-specific CD4 + T cells involved in alloimmunization., Study Design and Methods: We investigated the role of HLA molecules in platelet transfusion immunogenicity in a retrospective cohort study on men with specific anti-HLA who had undergone transfusion. We investigated the presence and phenotypic profile of HLA-specific CD4 + T cells in alloimmunized patients included in long-term platelet transfusion programs for hematologic malignancies., Results: More than 50% of the transfused subjects displayed an antibody response against HLA-B57 or -B58. HLA-B57-specific CD4 + T-cell responses were observed in patients alloimmunized against HLA-B57. Following specific stimulation, the patients presented HLA-specific CD4 + T cells producing tumor necrosis factor-α, interleukin (IL)-13, IL-17A, IL-2, IL-10, and IL-21., Conclusion: These results shed light on posttransfusion class I anti-HLA alloimmunization mechanisms and constitute a first step toward developing new strategies for reducing refractoriness., (© 2020 AABB.)

Alloimmunization against RBCs can cause life-threatening delayed hemolytic transfusion reactions. Anti-CD20 Ab has recently been used to prevent alloimmunization. However, its effects remain unclear, particularly in lymphoid organs. We investigated the impact of murine anti-CD20 Ab in the blood and spleen. We assessed protocols for preventing primary alloimmunization and for abolishing established alloimmunization. Prophylactic protocols prevented alloimmunization. However, anti-CD20 treatment could only limit the further amplification of established alloimmunization. Residual B cell subtype distribution was disrupted in the spleen, but adoptive transfer studies indicated that these cells were neither plasma nor memory cells. Anti-CD20 Ab had a major effect on alloreactive CD4 + T cells, increasing the expansion of this population and its CD40 expression, while lowering its CD134 expression, thereby confirming its role in alloimmunization. In conclusion, this study shows that anti-CD20 immunotherapy can prevent RBC Ab development. However, this immunotherapy is limited by the increase in alloreactive CD4 + T lymphocytes. Nevertheless, treatment with anti-CD20 Abs should be considered for patients requiring transfusion with a very high risk of alloimmunization and life-threatening complications., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Murine models of red blood cell transfusion show that inflammation associated with viruses or methylated DNA promotes red blood cell alloimmunization. In vaccination studies, the intensity of antigen-specific responses depends on the delay between antigen and adjuvant administration, with a short delay limiting immune responses. In mouse models of alloimmunization, the delay between the injection of Toll-like receptor agonists and transfusion is usually short. In this study, we hypothesized that the timing of Toll-like receptor 3 agonist administration affects red blood cell alloimmunization. Poly(I:C), a Toll-like receptor 3 agonist, was administered to B10BR mice at various time points before the transfusion of HEL-expressing red blood cells. For each time point, we measured the activation of splenic HEL-presenting dendritic cells, HEL-specific CD4(+) T cells and anti-HEL antibodies in serum. The phenotype of activated immune cells depended on the delay between transfusion and Toll-like receptor-dependent inflammation. The production of anti-HEL antibodies was highest when transfusion occurred 7 days after agonist injection. The proportion of HEL-presenting CD8α(+) dendritic cells producing interleukin-12 was highest in mice injected with poly(I:C) 3 days before transfusion. Although the number of early-induced HEL-specific CD4(+) T cells was similar between groups, a high proportion of these cells expressed CD134, CD40 and CD44 in mice injected with poly(I:C) 7 days before transfusion. This study clearly shows that the delay between transfusion and Toll-like receptor-induced inflammation influences the immune response to transfused red blood cells., (Copyright© Ferrata Storti Foundation.)

Alloimmunization against red blood cells (RBCs) is the main immunological risk associated with transfusion in patients with sickle cell disease (SCD). However, about 50-70% of SCD patients never get immunized despite frequent transfusion. In murine models, CD4(+) T cells play a key role in RBC alloimmunization. We therefore explored and compared the CD4(+) T-cell phenotypes and functions between a group of SCD patients (n = 11) who never became immunized despite a high transfusion regimen and a group of SCD patients (n = 10) who had become immunized (at least against Kidd antigen b) after a low transfusion regimen. We studied markers of CD4(+) T-cell function, including TLR, that directly control lymphocyte function, and their spontaneous cytokine production. We also tested responders for the cytokine profile in response to Kidd antigen b peptides. Low TLR2/TLR3 expression and, unexpectedly, strong expression of CD40 on CD4(+) T cells were associated with the nonresponder status, whereas spontaneous expression of IL-10 by CD4(+) T cells and weak Tbet expression were associated with the responder status. A Th17 profile was predominant in responders when stimulated by Jb(k) . These findings implicate CD4(+) T cells in alloimmunization in humans and suggest that they may be exploited to differentiate responders from nonresponders., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Sickle cell disease (SCD) is a chronic inflammatory disease associated with multiple organ damage, chronic anemia, and infections. SCD patients have a high rate of alloimmunization against red blood cells (RBCs) following transfusion and may develop autoimmune diseases. Studies in mouse models have suggested that regulatory T cells (Treg) play a role in alloimmunization against RBC antigens. We characterized the phenotype and function of the Treg cell population in a homogeneous cohort of transfused SCD patients. We found that the distribution of Treg subpopulations differed significantly between SCD patients and healthy blood donors. SCD patients have a particular Treg phenotype, with strong CTLA-4 and CD39 expression and weak HLA-DR and CCR7 expression. Finally, we show that this particular phenotype is related to SCD rather than alloimmunization status. Indeed, we observed no difference in Treg phenotype or function in vitro using autologous feeder cells between strong and weak responders to alloimmunization.

HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral therapy. To identify parameters of the CD4 response that may contribute to viral control rather than merely reflect a persistently low viremia, we compared the T helper profiles in two groups of patients with more than 10 years of viral suppression: HIV controllers from the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) CO18 cohort (n = 26) and efficiently treated patients (n = 16). Cells specific for immunodominant Gag and cytomegalovirus (CMV) peptides were evaluated for the production of 10 cytokines and cytotoxicity markers and were also directly quantified ex vivo by major histocompatibility complex (MHC) class II tetramer staining. HIV controller CD4(+) T cells were characterized by a higher frequency of gamma interferon (IFN-γ) production, perforin(+)/CD107a(+) expression, and polyfunctionality in response to Gag peptides. While interleukin 4 (IL-4), IL-17, and IL-21 production did not differ between groups, the cells of treated patients produced more IL-10 in response to Gag and CMV peptides, pointing to persistent negative immunoregulation after long-term antiretroviral therapy. Gag293 tetramer-positive cells were detected at a high frequency (0.12%) and correlated positively with IFN-γ-producing CD4(+) T cells in the controller group (R = 0.73; P = 0.003). Tetramer-positive cells were fewer in the highly active antiretroviral therapy (HAART) group (0.04%) and did not correlate with IFN-γ production, supporting the notion of a persistent immune dysfunction in HIV-specific CD4(+) T cells of treated patients. In conclusion, HIV controllers maintained a population of highly efficient Th1 effectors directed against Gag in spite of a persistently low antigenemia, while patients treated in the long term showed a loss of CD4 effector functions.

A small minority of HIV-infected individuals, known as HIV controllers, is able to exert long-term control over HIV replication in the absence of treatment. Increasing evidence suggests that the adaptive immune system plays a critical role in this control but also that a combination of several host and/or viral factors, rather than a single cause, leads to this rare phenotype. Here, we review recent advances in the study of these remarkable individuals. We summarize the epidemiology and clinical characteristics of HIV controllers, and subsequently describe contributing roles of host genetic factors, innate and adaptive immune responses, and viral factors to this phenotype. We emphasize distinctive characteristics of HIV-specific CD4 T cell responses and of CD4 T cell subpopulations that are frequently found in HIV controllers. We discuss major controversies in the field and the relevance of the study of HIV controllers for the development of novel therapeutic strategies and vaccines., (Copyright © 2011 Elsevier Inc. All rights reserved.)

More than 30 million people are infected by HIV worldwide. The rate of progression to AIDS is variable. A newly identified category of patients, so-called HIV controllers, spontaneously control HIV replication for long periods. HIV controllers are defined as infected patients whose viral load remains below 400 RNA copies/ml of blood, without treatment, for at least five years. We have studied the immune system of these patients, and particularly their CD4 lymphocytes, that participate in the induction, intensity, quality and duration of immune responses. CD4 lymphocytes in patients who progress to AIDS are directly targeted by the virus and participate in the activation that leads to immune deficiency. Central memory CD4 cells exhibit unusual properties in HIV controllers. Apart from the fact that they persist in large numbers and secrete large amounts of interleukin-2, which serves as an autocrine factor for their own growth, central memory CD4 cells overexpress the CCR7 homing molecule that allows them to leave capillaries and rapidly enter lymph nodes, the site of effective immune responses. These CD4 lymphocytes also men multiply rapidly, and some of them express receptors with very high antigen avidity. The presence of these central memory CD4 cells and their characteristic properties may explain the remarkable stability observed in HIV controllers. We suspect that these lymphocytes react very rapidly and efficiently to any breakthrough in viral replication. The putative relationship between HIV controllers and patients who remain asymptomatic and uninfected despite repeated exposure to the virus is discussed. Our new findings should help to guide antiretroviral therapy and vaccination strategies.

HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral treatment. Emerging evidence indicates that HIV control is mediated through very active cellular immune responses, though how such responses can persist over time without immune exhaustion is not yet understood. To investigate the nature of memory CD4+ T cells responsible for long-term anti-HIV responses, we characterized the growth kinetics, Vbeta repertoire, and avidity for antigen of patient-derived primary CD4+ T cell lines. Specific cell lines were obtained at a high rate for both HIV controllers (16/17) and efficiently treated patients (19/20) in response to the immunodominant Gag293 peptide. However, lines from controllers showed faster growth kinetics than those of treated patients. After normalizing for growth rates, IFN-gamma responses directed against the immunodominant Gag293 peptide showed higher functional avidity in HIV controllers, indicating differentiation into highly efficient effector cells. In contrast, responses to Gag161, Gag263, or CMV peptides did not differ between groups. Gag293-specific CD4+ T cells were characterized by a diverse Vbeta repertoire, suggesting that multiple clones contributed to the high avidity CD4+ T cell population in controllers. The high functional avidity of the Gag293-specific response could be explained by a high avidity interaction between the TCR and the peptide-MHC complex, as demonstrated by MHC class II tetramer binding. Thus, HIV controllers harbor a pool of memory CD4+ T cells with the intrinsic ability to recognize minimal amounts of Gag antigen, which may explain how they maintain an active antiviral response in the face of very low viremia.

Objectives: CCR7, a chemokine receptor expressed at high levels on naive and central memory T cells, is essential for T-cell recirculation into secondary lymphoid organs. We investigated CCR7 expression and chemotactic function in patient T cells, to gain further insights into mechanisms of T-cell dysfunction in HIV infection., Design and Methods: CCR7 expression and function were measured in T-cell subsets of viremic patients (n = 15), efficiently treated patients (n = 12), and healthy blood donors (n = 14). A whole blood assay was developed to measure chemotaxis in unperturbed T cells with physiological chemokine receptor expression levels., Results: The proportion of CCR7hi T-cell subsets (naive and central memory) was decreased in HIV-infected patients, but the expression of CCR7 within T-cell subsets did not differ from that in healthy controls. In spite of preserved CCR7 expression, CCR7-dependent chemotactic responses were significantly decreased within most T-cell subsets from viremic patients, including naive, central memory, and effector memory CD4 T cells and naive, central memory, and effector CD8 T cells. The chemotaxis defect was only partially corrected in efficiently treated patients. Importantly, chemotaxis to CXCR4, another chemokine receptor involved in T-cell recirculation, was preserved or even increased in T-cell subsets of HIV-infected patients., Conclusion: These findings provide evidence for an impairment of CCR7 function in patient T cells, which may have major consequences on T-cell recirculation. The fact that CXCR4 function was preserved points to a CCR7-specific functional defect rather than a general block in chemotaxis.

Human immunodeficiency virus (HIV) controllers are rare individuals who spontaneously control HIV type 1 replication for 10 years or more in the absence of antiretroviral treatment. In the present study, HIV controllers (n = 11) maintained potent HIV-specific CD4 responses in spite of very low antigenic loads. Their CD4+ central memory T (T(CM)) cells were characterized by near-normal numbers and preserved interleukin-2 (IL-2) secretion in response to HIV antigens and uniformly high expression of the survival receptor IL-7 receptor alpha (IL-7Ralpha). Controllers expressed CCR7 at higher levels than uninfected controls, suggesting differences in T(CM)-cell homing patterns. CD4+ effector memory T (T(EM))-cell responses were polyfunctional in HIV controllers, while IL-2 secretion was lost in viremic patients. Cytokine production was three times higher in controllers than in treated patients with undetectable viral loads, suggesting an intrinsically more efficient response in the former group. The total CD4+ T(EM)-cell pool underwent immune activation in controllers, as indicated by increased HLA-DR expression, decreased IL-7Ralpha expression, a bias towards gamma interferon production upon polyclonal stimulation, and increased macrophage inflammatory protein 1beta secretion associated with chronic CCR5 down-regulation. Thus, HIV controllers showed a preserved CD4+ T(CM)-cell compartment and signs of potent functional activation in the CD4+ T(EM)-cell compartment. While controllers did not show the generalized immune activation pattern associated with disease progression, they had signs of immune activation restricted to the effector compartment. These findings suggest the induction of an efficient, nondetrimental type of immune activation in patients who spontaneously control HIV.

In preclinical tumor model and in human cancer, tumor antigen specific T lymphocytes play a key role in the control of tumor development. Nevertheless in numerous cases, the infiltrating tumor T cells do not seem to influence the clinical progression of the tumor. A better phenotypic and functional characterization of T cells in close contact with tumor associated with a comprehensive analysis of tumor evasion mechanism to the host response should lead to an optimization of cancer immunotherapy protocols.

The widely administered Mycobacterium bovis BCG is an attractive live vector for the development of AIDS vaccines. We explored immune responses induced in cynomolgus macaques to rBCG-SIV(3), a mixture of three recombinant BCG strains expressing the SIVmac251 nef, gag and env genes. After a single intradermal (ID) inoculation, circulating blood cells from rBCG-SIV(3)-vaccinated monkeys exhibited CTL responses targeted against the three antigens and interferon-gamma (IFNgamma) secretion was observed. A rectal or oral boosting dose of rBCG-SIV(3) elicited anti-SIV IgAs in the rectum of vaccinated monkeys and increased IFNgamma secretion by circulating blood cells. Despite a good response against the vector, rBCG-SIV(3) administration did not induce IgG antibody responses or lymphoproliferation against the SIV antigens in blood. This could be due to the lack of in vivo persistence of the recombinant BCG strains that were used. Rectal challenge with fully pathogenic SIVmac251-infected all animals. However, after viral challenge, anti-SIV cellular and antibody responses were higher in rBCG-SIV(3) monkeys than in controls indicating that the vaccine induced anti-SIV CD4(+) T-cell memory.