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Original citation: J Clin Invest. 2015;125(11):4053-4062. https://doi.org/10.1172/JCI81187. Citation for this retraction: J Clin Invest. 2024;134(13):e183278. https://doi.org/10.1172/JCI183278. QIMR Berghofer Medical Research Institute recently notified the JCI of concerns regarding Figure 4B [...]

Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of [CD8.sup.+] T cells in tumor tissue as well as tumortissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not [CD8.sup.+] T cells. Moreover, [TIGIT.sup.+] Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings., Introduction T cell responses are controlled by multiple receptors: while costimulatory receptors ensure optimal T cell activation and proliferation to generate a protective immune response, coinhibitory or checkpoint receptors dampen [...]

The aim of this study is to categorize Turkish Instagram users in terms of their consumer behavior on social media, specifically Instagram, and in terms of conservatism as a way of life.. For this study, conservatism is defined as a thought process that focuses on values and traditions and generally opposes change. The study was undertaken to address the paucity of literature on the subject of conservatism as it relates to social media behavior. The face-to-face survey method was used to collect data from 288 Instagram users in Istanbul who were over the age of 18. A three-part questionnaire was administered with a research scale covering six key factors: opinion leadership, positive and negative word of mouth (WOM), information seeking, religion and obedience, women's status and rights, and family and sexual orientation. A five-point Likert-type scale was used to measure Instagram use and conservatism. After multivariate analysis, two clusters were identified. Cluster 1 includes 108 liberal respondents who do not use Instagram to share information, or to act as an opinion leader, or to make purchase decisions. These individuals are less religious, more individualistic, and more tolerant of women's rights. Cluster 2 includes 180 respondents with conservative lifestyles who actively use Instagram to express opinions and share and obtain positive and negative information about consumer brands before making a purchase decision. This cluster is less tolerant of women's rights and different sexual orientations. [ABSTRACT FROM AUTHOR]

Vaccines, arguably the single most important intervention in improving human health, have exploited the phenomenon of immunological memory. The elicitation of memory T cells is often an essential part of successful long-lived protective immunity. Our understanding of T cell memory has been greatly aided by the development of TCR Tg mice and MHC tetrameric staining reagents that have allowed the precise tracking of antigen-specific T cell responses. Indeed, following acute infection or immunization, naïveT cells undergo a massive expansion culminating in the generation of a robust effector T cell population. This peak effector response is relatively short-lived and, while most effector T cells die by r apoptosis, some remain and develop into memory cells. Although the molecular mechanisms underlying this cell fate decision remain incompletely defined, substantial progress has been made, particularly with regards to CD8+ T cells. For example, the effector CD8+ T cells generated during a response are heterogeneous, consisting of cells with more or less potential to develop into full-fledged memory cells. Development of CD8+ T cell memory is regulated by the transcriptional programs that control the differentiation and survival of effectorT cells. While the type of antigenic stimulation and level of inflammation control effector CD8+ T cell differentiation, availability of cytokines and their ability to control expression and function of Bcl-2 family members governs their survival. These distinct differentiation and survival programs may allow for finer therapeutic intervention to control both the quality and quantity of CD8+ T cell memory. Effector to memory transition of CD4+ T cells is less well characterized than CD8+ T cells, emerging details will be discussed.This review will focus on the recent progress made in our understanding of the mechanisms underlying the development of T cell memory with an emphasis on factors controlling survival of effector T cells. [ABSTRACT FROM AUTHOR]

Vaccines, arguably the single most important intervention in improving human health, have exploited the phenomenon of immunological memory. The elicitation of memory T cells is often an essential part of successful long-lived protective immunity. Our understanding of T cell memory has been greatly aided by the development of TCR Tg mice and MHC tetrameric staining reagents that have allowed the precise tracking of antigen-specific T cell responses. Indeed, following acute infection or immunization, naïve T cells undergo a massive expansion culminating in the generation of a robust effector T cell population. This peak effector response is relatively short-lived and, while most effector T cells die by apoptosis, some remain and develop into memory cells. Although the molecular mechanisms underlying this cell fate decision remain incompletely defined, substantial progress has been made, particularly with regards to CD8+ T cells. For example, the effector CD8+ T cells generated during a response are heterogeneous, consisting of cells with more or less potential to develop into full-fledged memory cells. Development of CD8+ T cell memory is regulated by the transcriptional programs that control the differentiation and survival of effector T cells. While the type of antigenic stimulation and level of inflammation control effector CD8+ T cell differentiation, availability of cytokines and their ability to control expression and function of Bcl-2 family members governs their survival. These distinct differentiation and survival programs may allow for finer therapeutic intervention to control both the quality and quantity of CD8+ T cell memory. Effector to memory transition of CD4+ T cells is less well characterized than CD8+ T cells, emerging details will be discussed. This review will focus on the recent progress made in our understanding of the mechanisms underlying the development of T cell memory with an emphasis on factors controlling survival of effector T cells. [ABSTRACT FROM AUTHOR]

As acute infections resolve, most effector CD8+ T cells die, whereas some persist and become memory T cells. Recent work showed that subsets of effector CD8+ T cells, identified by reciprocal expression of killer cell lectin-like receptor G1 (KLRG1) and CD127, have different lifespans. Similar to previous reports, we found that effector CD8+ T cells reported to have a longer lifespan (i.e., KLRG1lowCD127high) have increased levels of Bcl-2 compared with their shorter-lived KLRG1highCD127low counterparts. Surprisingly, we found that these effector KLRG1lowCD127high CD8+ T cells also had increased levels of Bim compared with KLRG1highCD127low cells. Similar effects were observed in memory cells, in which CD8+ central memory T cells expressed higher levels of Bim and Bcl-2 than did CD8+ effector memory T cells. Using both pharmacologic and genetic approaches, we found that survival of both subsets of effector and memory CD8+ T cells required Bcl-2 to combat the proapoptotic activity of Bim. Interestingly, inhibition or absence of Bcl-2 led to significantly decreased expression of Bim in surviving effector and memory T cells. In addition, manipulation of Bcl-2 levels by IL-7 or IL-15 also affected expression of Bim in effector CD8+ T cells. Finally, we found that Bim levels were significantly increased in effector CD8+ T cells lacking Bax and Bak. Together, these data indicate that cells having the highest levels of Bim are selected against during contraction of the response and that Bcl-2 determines the level of Bim that effector and memory T cells can tolerate. [ABSTRACT FROM AUTHOR]

Interleukin 7 (IL-7) and T cell antigen receptor signals have been proposed to be the main drivers of homeostatic T cell proliferation. However, it is not known why CD4+ T cells undergo less-efficient homeostatic proliferation than CD8+ T cells do. Here we show that systemic IL-7 concentrations increased during lymphopenia because of diminished use of IL-7 but that IL-7 signaling on IL-7 receptor-α–positive (IL-7Rα+) dendritic cells (DCs) in lymphopenic settings paradoxically diminished the homeostatic proliferation of CD4+ T cells. This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Rα+ DCs. Our results indicate that IL-7Rα+ DCs are regulators of the peripheral CD4+ T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4+ T cell population expansion in vivo. [ABSTRACT FROM AUTHOR]

The remarkable clinical success of cancer immunotherapies targeting the checkpoint receptors CTLA-4 and PD-1 has generated considerable excitement and emboldened efforts to build on this important foundation. Research efforts are now focused on understanding the mechanism of action of these immunotherapies, identifying new inhibitory mechanisms that could be targeted to achieve responses in patients with refractory cancers, and developing approaches that might exhibit efficacy against "immunologically inert" tumors. The outstanding challenges in moving forward are developing reliable strategies for determining which patients will respond optimally to a given immunotherapy, and what combination of immunotherapies and conventional therapies will prove beneficial against each tumor type. These issues were discussed in a one-day workshop at the SITC meeting in November 2014. [ABSTRACT FROM AUTHOR]

Coinhibitory receptors, such as CTLA-4 and PD-1, play a critical role in maintaining immune homeostasis by dampening T cell responses. Recently, they have gained attention as therapeutic targets in chronic disease settings where their dysregulated expression contributes to suppressed immune responses. The novel coinhibitory receptor TIGIT (T cell Ig and ITIM domain) has been shown to play an important role in modulating immune responses in the context of autoimmunity and cancer. However, the molecular mechanisms by which TIGIT modulates immune responses are still insufficiently understood. We have generated a panel of monoclonal anti-mouse TIGIT Abs that show functional properties in mice in vivo and can serve as important tools to study the underlying mechanisms of TIGIT function. We have identified agonistic as well as blocking anti-TIGITAb clones that are capable of modulating T cell responses in vivo. Administration of either agonist or blocking anti-TIGIT Abs modulated autoimmune disease severity whereas administration of blocking anti-TIGIT Abs synergized with anti-PD-1 Abs to affect partial or even complete tumor regression. The Abs presented in this study can thus serve as important tools for detailed analysis of TIGIT function in different disease settings and the knowledge gained will provide valuable insight for the development of novel therapeutic approaches targeting TIGIT. [ABSTRACT FROM AUTHOR]

CD3-engaging bispecific antibodies (BsAbs) enable the formation of an immune synapse between T cells and tumor cells, resulting in robust target cell killing not dependent on a preexisting tumor specific T cell receptor. While recent studies have shed light on tumor cell-specific factors that modulate BsAb sensitivity, the T cell-intrinsic determinants of BsAb efficacy and response durability are poorly understood. To better clarify the genes that shape BsAb-induced T cell responses, we conducted targeted analyses and a large-scale unbiased in vitro CRISPR/Cas9-based screen to identify negative regulators of BsAb-induced T cell proliferation. These analyses revealed that CD8+ T cells are dependent on CD4+ T cell-derived signaling factors in order to achieve sustained killing in vitro . Moreover, the mammalian target of rapamycin (mTOR) pathway and several other candidate genes were identified as intrinsic regulators of BsAb-induced T cell proliferation and/or activation, highlighting promising approaches to enhancing the utility of these potent therapeutics., Competing Interests: Authors RM, TF, GT, EC, DR, MP, JL, HW, and HL are currently employed by the Novartis Institutes for Biomedical Research (NIBR). The following authors were previously employed by NIBR when they were involved with the work described herein: MV (currently employed by Arbor Biotechnologies), GE (currently employed by Foghorn Therapeutics), MM (currently employed by Bristol Myers Squibb), and SK (currently employed by 2seventy Bio)., (Copyright © 2022 Molony, Funk, Trabucco, Corcoran, Ruddy, Varadarajan, Elliot, Piquet, Lam, Meyer, Wang, Kurtulus and Lu.)

Background: NIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors., Methods: Single agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 µg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, in an accelerated 3+3 dose escalation trial design. IL-15 and endogenous cytokines were monitored by ELISA and multiplexed electrochemiluminescent assays. Multiparameter flow cytometry assessed the frequency, phenotype and proliferation of peripheral blood mononuclear cells. Preliminary antitumor activity was assessed by overall response rate (Response Evaluation Criteria in Solid Tumors V.1.1)., Results: As of March 2, 2020, median treatment duration was 7.5 weeks (range 1.1-77.1). Thirteen patients had discontinued and one (uveal melanoma) remains on treatment with stable disease. Best clinical response was stable disease (3 of 14 patients; 21%). The most frequent adverse events (AEs) were circular erythematous injection site reactions (100%), chills (71%), fatigue (57%), and fever (50%). Treatment-related grade 3/4 AEs occurred in six participants (43%); treatment-related serious AEs (SAEs) in three (21%). The per-protocol maximum tolerated dose was not reached. Pharmacokinetic accumulation of serum IL-15 in the first week was followed by significantly lower levels in week 2, likely due to more rapid cytokine consumption by an expanding lymphocyte pool. NIZ985 treatment was associated with increases in several cytokines, including interferon (IFN)-γ, IL-18, C-X-C motif chemokine ligand 10, and tumor necrosis factor-β, plus significant induction of cytotoxic lymphocyte proliferation (including natural killer and CD8 + T cells), increased CD16 + monocytes, and increased CD163 + macrophages at injection sites., Conclusions: Subcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-γ and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy., Trial Registration Number: NCT02452268., Competing Interests: Competing interests: AV, CB, BKF, and GNP report inventorship in issued patents of relevance to this work (licensed to Novartis; managed by the National Cancer Institute) and other support by Novartis during the conduct of this study. DGM and TAW report other support from Novartis during the conduct of the study. JT reports grants from Alpine Biosciences, other support from Novartis during the conduct of the study, other support from Pfizer, Five Prime, Merck, Trillium, Incyte and Xencor outside of the current work, and personal fees from Regeneron, Aveo, Neoleukin, Seattle Genetics, BJ Biosciences, and Calithera outside of the current work. SG reports other support from Novartis during the conduct of the study, other support from Bristol Myers Squibb, Rexahn, Incyte, LSK, Five Prime, Mirati, QED, Debiopharm, Merck, Pfizer, AstraZeneca, Medimmune, Clovis, and Seattle Genetics outside of the current work, and ownership of stock in Salerius Pharmaceuticals by spouse. RL reports grants and personal fees from Bristol Myers Squibb, personal fees from Merck, Oncolys, and Sanofi, and non-financial support from Clinigen outside of the current work. NSP, DL, SK, LHL, NRC and FB are, or were at the time of the work described, employees of Novartis Pharmaceuticals. KC, DCW, CJP, WF, ELP, MR and AW-G report nothing to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

p53 is a transcription factor that plays a central role in guarding the genomic stability of cells through cell-cycle arrest or induction of apoptosis. However, the effects of p53 in antitumor immunity are poorly understood. To investigate the role of p53 in controlling tumor-immune cell cross-talk, we studied murine syngeneic models treated with HDM201, a potent and selective second-generation MDM2 inhibitor. In response to HDM201 treatment, the percentage of dendritic cells increased, including the CD103 + antigen cross-presenting subset. Furthermore, HDM201 increased the percentage of Tbet + Eomes + CD8 + T cells and the CD8 + /Treg ratio within the tumor. These immunophenotypic changes were eliminated with the knockout of p53 in tumor cells. Enhanced expression of CD80 on tumor cells was observed in vitro and in vivo , which coincided with T-cell-mediated tumor cell killing. Combining HDM201 with PD-1 or PD-L1 blockade increased the number of complete tumor regressions. Responding mice developed durable, antigen-specific memory T cells and rejected subsequent tumor implantation. Importantly, antitumor activity of HDM201 in combination with PD-1/PD-L1 blockade was abrogated in p53-mutated and knockout syngeneic tumor models, indicating the effect of HDM201 on the tumor is required for triggering antitumor immunity. Taken together, these results demonstrate that MDM2 inhibition triggers adaptive immunity, which is further enhanced by blockade of PD-1/PD-L1 pathway, thereby providing a rationale for combining MDM2 inhibitors and checkpoint blocking antibodies in patients with wild-type p53 tumors. SIGNIFICANCE: This study provides a mechanistic rationale for combining checkpoint blockade immunotherapy with MDM2 inhibitors in patients with wild-type p53 tumors., (©2021 American Association for Cancer Research.)

The low frequency of T cells specific for given antigens makes the study of antigen-specific T cell responses difficult. The development of MHC class I and II tetramer staining techniques allows precise quantification and tracking of antigen-specific CD8(+) and CD4(+) T cell responses. Here, we describe a protocol for MHC class I and II tetramer staining of mouse T cells isolated from various tissues of mice infected with lymphocytic choriomeningitis virus (LCMV) or with murine cytomegalovirus (MCMV).

The thymus generates T cells with diverse specificities and functions. To assess the contribution of cytokine receptors to the differentiation of T cell subsets in the thymus, we constructed conditional knockout mice in which IL-7Rα or common cytokine receptor γ chain (γ(c)) genes were deleted in thymocytes just before positive selection. We found that γ(c) expression was required to signal the differentiation of MHC class I (MHC-I)-specific thymocytes into CD8(+) cytotoxic lineage T cells and into invariant natural killer T cells but did not signal the differentiation of MHC class II (MHC-II)-specific thymocytes into CD4(+) T cells, even into regulatory Foxp3(+)CD4(+) T cells which require γ(c) signals for survival. Importantly, IL-7 and IL-15 were identified as the cytokines responsible for CD8(+) cytotoxic T cell lineage specification in vivo. Additionally, we found that small numbers of aberrant CD8(+) T cells expressing Runx3d could arise without γ(c) signaling, but these cells were developmentally arrested before expressing cytotoxic lineage genes. Thus, γ(c)-transduced cytokine signals are required for cytotoxic lineage specification in the thymus and for inducing the differentiation of MHC-I-selected thymocytes into functionally mature T cells.

During an immune response, most effector T cells die, whereas some are maintained and become memory T cells. Factors controlling the survival of effector CD4(+) and CD8(+) T cells remain unclear. In this study, we assessed the role of IL-7, IL-15, and their common signal transducer, STAT5, in maintaining effector CD4(+) and CD8(+) T cell responses. Following viral infection, IL-15 was required to maintain a subpopulation of effector CD8(+) T cells expressing high levels of killer cell lectin-like receptor subfamily G, member 1 (KLRG1), and lower levels of CD127, whereas IL-7 and IL-15 acted together to maintain KLRG1(low)CD127(high) CD8(+) effector T cells. In contrast, effector CD4(+) T cell numbers were not affected by the individual or combined loss of IL-15 and IL-7. Both IL-7 and IL-15 drove phosphorylation of STAT5 within effector CD4(+) and CD8(+) T cells. When STAT5 was deleted during the course of infection, both KLRG1(high)CD127(low) and KLRG1(low)CD127(high) CD8(+) T cells were lost, although effector CD4(+) T cell populations were maintained. Furthermore, STAT5 was required to maintain expression of Bcl-2 in effector CD8(+), but not CD4(+), T cells. Finally, IL-7 and IL-15 required STAT5 to induce Bcl-2 expression and to maintain effector CD8(+) T cells. Together, these data demonstrate that IL-7 and IL-15 signaling converge on STAT5 to maintain effector CD8(+) T cell responses.