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Introduction of complement (C) inhibition into clinical practice has revolutionized the treatment of patients with complement-mediated atypical hemolytic syndrome (aHUS). Our C3 D1115N mouse model, engineered around a gain of function point mutation in C3, is associated with complement mediated aHUS in man, allowing us to study the clinical disease in a preclinical model. Backcrossing our model onto C7 deficient and C5aR1 deficient mice enabled further determination of the roles of the C5a-C5aR1 axis and C5b-9 (the membrane attack complex) on kidney disease. C7 deficiency completely abolished both clinical and histological evidence of disease. Removing C5aR1 (CD88) attenuated the risk of developing clinical disease, but mice still developed thrombotic microangiopathy. Therapeutic inhibition strengthened our genetic findings showing both anti-C7 therapy and an oral C5aR1 antagonist, when used before evidence of significant kidney injury, prevented mice from succumbing to disease. However, there was ongoing histological disease within mice treated with the C5aR1 antagonist. Our data suggest that both C5aR1 and C7 play a role in the development of the conditions required for thrombotic microangiopathy of the kidney. While disrupting the C5a-C5aR1 axis is beneficial, our genetic and therapeutic studies showed that thrombotic microangiopathy of the kidney can still develop and ultimately our data confirm that the membrane attack complex is required to develop thrombotic microangiopathy of the kidney. Overall, our study shows that in addition to requiring alternative pathway dysregulation, local generation of membrane attack complex within the kidney is also critical to drive disease pathology in complement-mediated aHUS., (Copyright © 2025 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Addressing inflammation, demyelination, and associated neurodegeneration in inflammatory demyelinating diseases like multiple sclerosis (MS) remains challenging. ACT-1004-1239, a first-in-class and potent ACKR3 antagonist, currently undergoing clinical development, showed promise in preclinical MS models, reducing neuroinflammation and demyelination. However, its effectiveness in treating established disease and impact on remyelination after the occurrence of demyelinated lesions remain unexplored. This study assessed the therapeutic effect of ACT-1004-1239 in two demyelinating disease models. In the proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) model, ACT-1004-1239 administered upon the detection of the first signs of paralysis, resulted in a dose-dependent reduction in EAE disease severity, concomitant with diminished immune cell infiltrates in the CNS and reduced demyelination. Notably, efficacy correlated with elevated plasma concentrations of CXCL11 and CXCL12, two pharmacodynamic biomarkers of ACKR3 antagonism. Combining ACT-1004-1239 with siponimod, an approved immunomodulatory treatment for MS, synergistically reduced EAE severity. In the cuprizone-induced demyelination model, ACT-1004-1239 administered after 5 weeks of cuprizone exposure, significantly accelerated remyelination, already quantifiable one week after cuprizone withdrawal. Additionally, ACT-1004-1239 penetrated the CNS, elevating brain CXCL12 concentrations. These results demonstrate that ACKR3 antagonism significantly reduces the severity of experimental demyelinating diseases, even when treatment is initiated therapeutically, after the occurrence of lesions. It confirms the dual mode of action of ACT-1004-1239, exhibiting both immunomodulatory effects by reducing neuroinflammation and promyelinating effects by accelerating myelin repair. The results further strengthen the rationale for evaluating ACT-1004-1239 in clinical trials for patients with demyelinating diseases., (© 2024. The Author(s).)

Treatment of patients with recent-onset type 1 diabetes with an anti-CD3 antibody leads to the transient stabilization of C-peptide levels in responder patients. Partial efficacy may be explained by the entry of islet-reactive T-cells spared by and/or regenerated after the anti-CD3 therapy. The CXCR3/CXCL10 axis has been proposed as a key player in the infiltration of autoreactive T cells into the pancreatic islets followed by the destruction of β cells. Combining the blockade of this axis using ACT-777991, a novel small-molecule CXCR3 antagonist, with anti-CD3 treatment may prevent further infiltration and β-cell damage and thus, preserve insulin production. The effect of anti-CD3 treatment on circulating T-cell subsets, including CXCR3 expression, in mice was evaluated by flow cytometry. Anti-CD3/ACT-777991 combination treatment was assessed in the virally induced RIP-LCMV-GP and NOD diabetes mouse models. Treatments started at disease onset. The effects on remission rate, blood glucose concentrations, insulitis, and plasma C-peptide were evaluated for the combination treatment and the respective monotherapies. Anti-CD3 treatment induced transient lymphopenia but spared circulating CXCR3+ T cells. Combination therapy in both mouse models synergistically and persistently reduced blood glucose concentrations, resulting in increased disease remission rates compared to each monotherapy. At the study end, mice in disease remission demonstrated reduced insulitis and detectable plasma C-peptide levels. When treatments were initiated in non-severely hyperglycemic NOD mice at diabetes onset, the combination treatment led to persistent disease remission in all mice. These results provide preclinical validation and rationale to investigate the combination of ACT-777991 with anti-CD3 for the treatment of patients with recent-onset diabetes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology.)

The CXCR3 chemokine receptor is a G protein-coupled receptor mainly expressed on immune cells from the lymphoid lineage, including activated T cells. Binding of its inducible chemokine ligands CXCL9, CXCL10, and CXCL11 leads to downstream signaling events and the migration of activated T cells to sites of inflammation. Herein, we report the third part of our CXCR3 antagonist program in the field of autoimmunity, culminating in the discovery of the clinical compound ACT-777991 ( 8a ). A previously disclosed advanced molecule was exclusively metabolized by the CYP2D6 enzyme, and options to address the issue are described. ACT-777991 is a highly potent, insurmountable, and selective CXCR3 antagonist that showed dose-dependent efficacy and target engagement in a mouse model of acute lung inflammation. The excellent properties and safety profile warranted progress in the clinics.

Background: Sjögren's syndrome is a systemic autoimmune disease characterized by immune cells predominantly infiltrating the exocrine glands and frequently forming ectopic lymphoid structures. These structures drive a local functional immune response culminating in autoantibody production and tissue damage, associated with severe dryness of mucosal surfaces and salivary gland hypofunction. Cenerimod, a potent, selective and orally active sphingosine-1-phosphate receptor 1 modulator, inhibits the egress of lymphocytes into the circulation. Based on the mechanism of action of cenerimod, its efficacy was evaluated in two mouse models of Sjögren's syndrome., Methods: Cenerimod was administered in two established models of Sjögren's syndrome; firstly, in an inducible acute viral sialadenitis model in C57BL/6 mice, and, secondly, in the spontaneous chronic sialadenitis MRL/lpr mouse model. The effects of cenerimod treatment were then evaluated by flow cytometry, immunohistochemistry, histopathology and immunoassays. Comparisons between groups were made using a Mann-Whitney test., Results: In the viral sialadenitis model, cenerimod treatment reduced salivary gland immune infiltrates, leading to the disaggregation of ectopic lymphoid structures, reduced salivary gland inflammation and preserved organ function. In the MRL/lpr mouse model, cenerimod treatment decreased salivary gland inflammation and reduced T cells and proliferating plasma cells within salivary gland ectopic lymphoid structures, resulting in diminished disease-relevant autoantibodies within the salivary glands., Conclusions: Taken together, these results suggest that cenerimod can reduce the overall autoimmune response and improve clinical parameters in the salivary glands in models of Sjögren's syndrome and consequently may reduce histological and clinical parameters associated with the disease in patients., (© 2021. The Author(s).)

Loss of control in the trafficking of immune cells to the inflamed lung tissue contributes to the pathogenesis of life-threatening acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). Targeting CXCR7 has been proposed as a potential therapeutic approach to reduce pulmonary inflammation; however, its role and its crosstalk with the two chemokine receptors CXCR3 and CXCR4 via their shared ligands CXCL11 and CXCL12 is not yet completely understood. The present paper aimed to characterize the pathological role of the CXCR3/CXCR4/CXCR7 axis in a murine model of ALI. Lipopolysaccharide (LPS) inhalation in mice resulted in the development of key pathologic features of ALI/ARDS, including breathing dysfunctions, alteration in the alveolar capillary barrier, and lung inflammation. LPS inhalation induced immune cell infiltration into the bronchoalveolar space, including CXCR3 + and CXCR4 + cells, and enhanced the expression of the ligands of these two chemokine receptors. The first-in-class CXCR7 antagonist, ACT-1004-1239, increased levels of CXCL11 and CXCL12 in the plasma without affecting their levels in inflamed lung tissue, and consequently reduced CXCR3 + and CXCR4 + immune cell infiltrates into the bronchoalveolar space. In the early phase of lung inflammation, characterized by a massive influx of neutrophils, treatment with ACT-1004-1239 significantly reduced the LPS-induced breathing pattern alteration. Both preventive and therapeutic treatment with ACT-1004-1239 reduced lung vascular permeability and decreased inflammatory cell infiltrates. In conclusion, these results demonstrate a key pathological role of CXCR7 in ALI/ARDS and highlight the clinical potential of ACT-1004-1239 in ALI/ARDS pathogenesis., Competing Interests: Authors LP, AS, NB, MT, DS, FL, and MM were employed by the company Idorsia Pharmaceuticals Ltd., (Copyright © 2021 Pouzol, Sassi, Baumlin, Tunis, Strasser, Lehembre and Martinic.)

Current strategies for the treatment of demyelinating diseases such as multiple sclerosis (MS) are based on anti-inflammatory or immunomodulatory drugs. Those drugs have the potential to reduce the frequency of new lesions but do not directly promote remyelination in the damaged central nervous system (CNS). Targeting CXCR7 (ACKR3) has been postulated as a potential therapeutic approach in demyelinating diseases, leading to both immunomodulation by reducing leukocyte infiltrates and promyelination by enhancing myelin repair. ACT-1004-1239 is a potent, selective, insurmountable, and orally available first-in-class CXCR7 receptor antagonist. The effect of ACT-1004-1239 was evaluated in the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and the cuprizone-induced demyelination mouse models. In addition, ACT-1004-1239 was assessed in a rat oligodendrocyte precursor cell (OPC) differentiation assay in vitro. In the MOG-induced EAE model, ACT-1004-1239 treatment (10-100 mg/kg, twice daily, orally) showed a significant dose-dependent reduction in disease clinical scores, resulting in increased survival. At the highest dose tested (100 mg/kg, twice daily), ACT-1004-1239 delayed disease onset and significantly reduced immune cell infiltrates into the CNS and plasma neurofilament light chain concentration. Treatment with ACT-1004-1239 dose-dependently increased plasma CXCL12 concentration, which correlated with a reduction of the cumulative disease score. Furthermore, in the cuprizone model, ACT-1004-1239 treatment significantly increased the number of mature myelinating oligodendrocytes and enhanced myelination in vivo. In vitro, ACT-1004-1239 promoted the maturation of OPCs into myelinating oligodendrocytes. These results provide evidence that ACT-1004-1239 both reduces neuroinflammation and enhances myelin repair substantiating the rationale to explore its therapeutic potential in a clinical setting., (© 2021 Idorsia Pharmaceuticals Ltd. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Competing Interests: Competing interests: DSS, SF, VS, EG, UG, GP, EV, AKS, BR, JR, AH, UM, PMAG, MPK, MMM, and MJM are employees of Idorsia Pharmaceuticals Ltd. MT, grant research support.

Background: Despite the recent approval of new oral therapies for the treatment of multiple sclerosis (MS), a significant percentage of patients are still not free from disease activity. In view of the complex pathogenesis and the relapsing and progressive nature of MS, combination therapy, a classical approach to treat many chronic diseases, could improve disease control over monotherapy. Ponesimod, a selective and rapidly reversible sphingosine-1-phosphate receptor Type 1 (S1P1) modulator, currently in Phase III clinical trial stage in relapsing MS (RMS), and dimethyl fumarate (DMF) would potentially be an ideal combination due to their differing mechanisms of action and oral administration. Objective: The goal of the study was to evaluate the therapeutic effect of ponesimod monotherapy and investigate the potential additive, or synergistic, activity of ponesimod-DMF combination therapy in experimental autoimmune encephalomyelitis (EAE) animal models of MS. Methods: Efficacy was evaluated in the myelin oligodendrocyte glycoprotein (MOG)-induced EAE model in C57BL/6 mice (ponesimod monotherapy) and in the myelin basic protein (MBP)-induced EAE model in Lewis rats (monotherapies and combination therapy). The principal readout was the clinical score assessing paralysis. Additional readouts, such as histopathology, survival, and disease prevalence, were generated in parallel when applicable. Results: Ponesimod monotherapy in the mouse EAE model showed significant efficacy in both preventative and therapeutic settings. In the rat EAE model, ponesimod demonstrated significant dose-dependent efficacy on clinical scores, while DMF showed only modest activity. Combination therapy synergistically reduced the severity and prevalence of disease. Only the combination treatment of ponesimod and DMF fully suppressed clinical disease activity by the end of the study. Conclusion: The results support the potential therapeutic benefits of combining ponesimod with DMF to improve disease activity control in patients with MS. Additionally, the results suggest that combining ponesimod with other oral agents that have different mechanisms of action might also be therapeutically beneficial to patients with MS., Competing Interests: FUNDING:No funding was provided. DISCLOSURES:The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Drs. Pouzol, Piali, Steiner, and Clozel acknowledge that the work was performed as employees of Actelion Pharmaceuticals Ltd. During manuscript preparation, Actelion Pharmaceuticals Ltd. was acquired by Johnson & Johnson, and its drug discovery and early development activities subsequently transferred into a newly created company, Idorsia Pharmaceuticals Ltd.

Nucleotide-binding and oligomerization domain (NOD)-like receptors NOD1 and NOD2 are cytosolic innate immune receptors that recognize microbial peptidoglycans. Although studies have addressed the role of NOD proteins in innate immune responses, little attention has been given to their impact on the developing adaptive immune system. We have assessed the roles of NOD1 and NOD2 deficiency on T cell development in mice. Our results demonstrate that NOD1 and NOD2 promote the positive selection/maturation of CD8 single-positive thymocytes in a thymocyte-intrinsic manner. TCR-mediated ERK phosphorylation is significantly reduced in the absence of NOD proteins, but receptor-interacting protein 2 is not involved in CD8 single-positive thymocyte selection or ERK signaling. Commensal bacteria-free animals have thymocyte maturation defects, and exogenous NOD ligands can enhance thymocyte maturation in culture. These results raise the intriguing possibility that abnormal lymphocyte responses observed in NOD-dependent inflammatory diseases are not driven solely by microbial signals in the gut, but may also involve intrinsic lymphocyte defects resulting from impaired CD8 T cell thymic development., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of beta cells in the pancreas. Little is known about the in vivo dynamic interactions between T cells and beta cells or the kinetic behavior of other immune cell subsets in the pancreatic islets. Utilizing multiphoton microscopy we have designed a technique that allows for the real-time visualization of diabetogenic T cells and dendritic cells in pancreatic islets in a live animal, including their interplay with beta cells and the vasculature. Using a custom designed stage, the pancreas was surgically exposed under live conditions so that imaging of islets under intact blood pressure and oxygen supply became possible. We demonstrate here that this approach allows for the tracking of diabetogenic leukocytes as well as vascularization phenotype of islets and accumulation of dendritic cells in islets during diabetes pathogenesis. This technique should be useful in mapping crucial kinetic events in T1D pathogenesis and in testing the impact of immune based interventions on T cell migration, extravasation and islet destruction.

It is not fully understood how the expression level of autoantigens in beta cells impacts autoimmune diabetes (T1D) development. Earlier studies using ovalbumin and also insulin had shown that secreted antigens could enhance diabetes development through facilitated presentation by antigen presenting cells. Here we sought to determine how the expression level of a membrane bound, non-secreted or cross-presented neo-antigen, the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), would influence T1D. We found that an RIP-LCMV transgenic mouse line exhibiting higher levels of beta cell GP expression developed more severe diabetes after LCMV infection or transfer of high numbers of activated autoreactive T cells. Importantly, all beta cells were lost and a significant increase in morbidity and mortality from T1D was noted. Insulitis and accumulation of autoaggressive CD8 cells was more profound in the RIP-LCMV-GP high-expressor line. Interestingly, the additional introduction of neo-antigen-specific CD4(+) helper or regulatory T cells was able to influence diabetogenesis positively or negatively. We conclude that a higher degree of autoantigen expression results in increased diabetes susceptibility. Therefore, autoantigens such as insulin that are expressed at higher levels in beta cells might have a more profound impact on diabetes pathogenesis., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Infection with viruses that have the capacity to modulate or evade the immune response can result in persistence, which can lead to a variety of chronic problems including neoplasia, immunosuppression, autoimmune-like syndromes, and selective organ failure. Recently, two promising new treatment approaches that target either the inhibitory receptor programmed cell death 1 (PD-1) or neutralize interleukin-10 (IL-10) during chronic viral infection have been described. We discuss how future combination therapies can be used to inhibit viral synthesis as well as strengthen the antiviral response without increasing immunopathology or the development of autoimmune disease.

Type 1 diabetes (T1D) is the most common autoimmune disease affecting almost 20 million people worldwide. T1D is thought to be caused by autoaggressive T cells infiltrating pancreatic islets and destroying insulin-producing beta cells. Because insulin therapy, the current treatment for T1D, does not protect against all late complications and because life expectancy is affected, researchers are searching for preventive or curative approaches that block or prevent immune-mediated islet destruction. However, the precise in vivo events that take place in islets during T1D development remain unknown. During the past decade, 2-photon microscopy (2PM) has emerged as a new technique to assess cell-cell interactions in real-time and at high resolution in vivo. This technique has been demonstrated recently to be a promising tool to study the progressive development of T1D pathogenesis at the cellular level. In this review, we propose a new surgical and immunological approach so that 2PM can be utilized to monitor the duration that effector cells reside within an islet, determine the number of effector cells needed for elimination of beta cells, and follow the fate of beta cells when regulatory cells are present. Understanding the cellular dynamics during T1D development is critical for the rational design of immunotherapies.

During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such "antigenic spreading" can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic beta-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo-expressed beta-cell autoantigens will not accelerate autoimmunity unless large numbers of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present.

A defining characteristic of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses cellular immune responses by modulating the function of T cells and antigen-presenting cells. In this paper, we report that IL-10 production is drastically increased in mice persistently infected with lymphocytic choriomeningitis virus. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid resolution of the persistent infection. IL-10 secretion was diminished and interferon gamma production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8alpha+ dendritic cell (DC) numbers declined early after infection, whereas CD8alpha- DC numbers were not affected. CD8alpha- DCs supported IL-10 production and subsequent dampening of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10-mediated immune suppression, preventing IL-10 priming by CD8alpha- DCs and enhancing antiviral responses and thereby resolving infection without causing immunopathology.

The role of nonthymic epithelial (non-TE) MHC in T cell repertoire selection remains controversial. To analyze the relative roles of thymic epithelial (TE) and non-TE MHC in T cell repertoire selection, we have generated tetraparental aggregation chimeras (B6-nude<=>BALB/c and B6<=>BALB/c-nude) harboring T and B cells from both parents, whereas TE cells originated exclusively from the non-nude donor. These chimeras mounted protective virus-specific TE and non-TE MHC-restricted T cell responses. To further evaluate whether non-TE MHC alone was sufficient to generate a functional T cell repertoire, we generated tetraparental aggregation chimeras lacking MHC class II (B6-nude<=>MHCII(-/-)) or both MHC molecules (B6-nude<=>MHCI(-/-)II(-/-)) on TE cells, but not on cells of B6-nude origin. Chimeras with MHC-deficient TE cells mounted functional virus-specific CD8+ but not CD4+ T cell responses. Thus, maturation of functional CD4+ T cell responses required MHC class II on thymic epithelium, whereas CD8+ T cells matured in the absence of TE MHC.

Regulatory T cells (Tregs) are essential to suppress harmful self-reactive T cell responses. A paper in this issue of the European Journal of Immunology analyzes the role of Tregs in preventing syngeneic graft-versus-host disease (sGVHD). In this Commentary, we address the role of antigen specificity of Tregs in this context as well as future protocols for successful allogeneic grafts transplantation. Such ideal interventions will hopefully retain a diverse repertoire of pathogen-specific T cells, while maintenance of self-, foreign- and alloantigen-specific Tregs ensures life-long graft tolerance.

If present in sufficient numbers, could extrathymic T cells substitute for thymus-derived T cells? To address this issue, we studied extrathymic T cells that develop in athymic mice under the influence of oncostatin M (OM). In this model, extensive T-cell development is probably due to amplification of a minor pathway of T-cell differentiation taking place only in the lymph nodes. Extrathymic CD4 T cells expanded poorly and were deficient in providing B-cell help after infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). Compared with classic T cells, stimulated extrathymic CD8 T cells produced copious amounts of interferon gamma (IFN-gamma), and their expansion was precocious but of limited amplitude because of a high apoptosis rate. Consequently, although extrathymic cytotoxic T lymphocytes (CTLs) responded to LCMV infection, as evidenced by the expansion of GP33-41 tetramer-positive CD8 T cells, they were unable to eradicate the virus. Our data indicate that the site of development impinges on T-cell quality and function and that extrathymic T cells functionally cannot substitute for classical thymic T cells.

H-Y-specific T cell receptor (TCR) transgenic mice express an MHC class I H-2D(b)-restricted TCR specific for a male antigen-derived peptide (H-Y). Selection and survival of cells expressing this low-affinity TCR were analyzed under optimal and sub-optimal conditions. Optimal conditions were provided by a thymic environment with high H-2D(b) density. Sub-optimal conditions were provided by a thymic environment with decreased H-2D(b) density or by an athymic environment with either high or low H-2D(b) density. Whereas negative selection was still guaranteed under sub-optimal conditions, selection and survival efficiency of cells expressing the transgenic TCR were strongly dependent on optimal conditions. These results indicated that both a thymic microenvironment and a high density of TCR-restricting MHC molecules were needed to ensure selection and maintenance of cells expressing TCR with low affinity and hence a more diverse T cell repertoire.

Nonthymic epithelial cells were compared with thymic epithelial cells for their role in T cell repertoire selection. Tetraparental aggregation chimeras were generated from T and B cell-deficient mice (H-2(d) SCID or H-2(b) Rag-/-) and thymus-deficient nude mice (H-2(b) or H-2(d)). These tetraparental mice showed primary protective CD8(+) T cell responses, after lymphocytic choriomeningitis virus infection, that were peptide-specifically restricted to either thymic or nonthymic epithelial MHC at comparable levels. These chimeras also mounted neutralizing IgG responses dependent on cognate CD4(+) T helper cell activity restricted to nonthymic epithelial MHC. Therefore, in contrast to earlier results with irradiation or thymus chimeras, these relatively undisturbed tetraparental mice reveal that the MHC of nonthymic epithelial cells efficiently selects a functional T cell repertoire.

Altered peptide ligands (APLs) and their antagonistic or partial agonistic character-influencing T cell activation have mainly been studied in vitro Some studies have shown APLs as a viral escape mechanism from cytotoxic CD8(+) T cell responses in vivo. However, whether infection or superinfection with a virus displaying an antagonistic T cell epitope can alter virus-host relationships via inhibiting T cell-mediated immunopathology is unclear. Here, we evaluated a recently described CD4(+) T cell escape lymphocytic choriomeningitis virus (LCMV) variant that in vitro displayed antagonistic characteristics for the major histocompatibility complex class II-restricted mutated epitope. Mice transgenic for the immunodominant LCMV-specific T helper epitope that usually succumb to wild-type LCMV-induced immunopathology, survived if they were simultaneously coinfected with antagonistic variant but not with control virus. The results illustrate that a coinfecting APL-expressing virus can shift an immunopathological virus-host relationships in favor of host survival. This may play a role in poorly cytopathic long-lasting virus carrier states in humans.