scholarly journals A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response

2021 ◽  
Author(s):  
Kelli A. Connolly ◽  
Manik Kuchroo ◽  
Aarthi Venkat ◽  
Achia Khatun ◽  
Jiawei Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tumor Development ◽  
Terminal Differentiation ◽  
Critical Function ◽  
Cell Responses ◽  
Draining Lymph Node ◽  
Lcmv Infection

Abstract“Stem-like” TCF1+ CD8+ T cells (TSL) are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy but, as tumors contain signals that should drive T-cell terminal-differentiation, how these cells are maintained in tumors remains unclear. We found that a small number of TCF1+ tumor-specific CD8+ T cells were present in tumors throughout development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from “hot” to “cold”. By contrast, most tumor-specific CD8+ T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSL from chronic LCMV infection and this population was stable over time, despite the changes in the TME. dLN T cells were the precursors of their more-differentiated intratumoral counterparts, and maintenance of TCF1 by intratumoral T cells required continuous migration from dLNs. Finally, TSL CD8 T cells were also present in LNs from lung adenocarcinoma patients, suggesting this population is also relevant in human disease. Thus, we propose that the dLN TSL reservoir has a critical function during tumor development in sustaining antitumor T cells during tumor development and protecting them from the terminal differentiation that occurs in the TME.

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

scholarly journals SARS-CoV-2-specific T cells exhibit phenotypic features reflecting robust helper function, lack of terminal differentiation, and high proliferative potential

2020 ◽  
Author(s):  
Jason Neidleman ◽  
Xiaoyu Luo ◽  
Julie Frouard ◽  
Guorui Xie ◽  
Gurjot Gill ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Terminal Differentiation ◽  
Proliferative Potential ◽  
Th1 Cells ◽  
Cell Responses ◽  
Cell Immunity ◽  
Helper Function ◽  
Phenotypic Features

ABSTRACTConvalescing COVID-19 patients mount robust T cell responses against SARS-CoV-2, suggesting an important role for T cells in viral clearance. To date, the phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Using 38-parameter CyTOF, we phenotyped longitudinal specimens of SARS-CoV-2-specific CD4+ and CD8+ T cells from nine individuals who recovered from mild COVID-19. SARS-CoV-2-specific CD4+ T cells were exclusively Th1 cells, and predominantly Tcm with phenotypic features of robust helper function. SARS-CoV-2-specific CD8+ T cells were predominantly Temra cells in a state of less terminal differentiation than most Temra cells. Subsets of SARS-CoV-2-specific T cells express CD127, can homeostatically proliferate, and can persist for over two months. Our results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection, and support an important role for SARS-CoV-2-specific T cells in host control of COVID-19.

scholarly journals A Role for Perforin in Downregulating T-Cell Responses during Chronic Viral Infection

1999 ◽  
Vol 73 (3) ◽  
pp. 2527-2536 ◽  
Author(s):  
Mehrdad Matloubian ◽  
M. Suresh ◽  
Alison Glass ◽  
Marisa Galvan ◽  
Kit Chow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Chronic Viral Infection ◽  
Persistently Infected ◽  
Cell Responses ◽  
Immune Mediated ◽  
Lcmv Infection

ABSTRACT Cytotoxic T cells secrete perforin to kill virus-infected cells. In this study we show that perforin also plays a role in immune regulation. Perforin-deficient (perf −/−) mice chronically infected with lymphocytic choriomeningitis virus (LCMV) contained greater numbers of antiviral T cells compared to persistently infected +/+ mice. The enhanced expansion was seen in both CD4 and CD8 T cells, but the most striking difference was in the numbers of LCMV-specific CD8 T cells present in infected perf −/− mice. Persistent LCMV infection of +/+ mice results in both deletion and anergy of antigen-specific CD8 T cells, and our results show that this peripheral “exhaustion” of activated CD8 T cells occurred less efficiently in perf −/− mice. This excessive accumulation of activated CD8 T cells resulted in immune-mediated damage in persistently infected perf −/− mice; ∼50% of these mice died within 2 to 4 weeks, and mortality was fully reversed by in vivo depletion of CD8 T cells. This finding highlights an interesting dichotomy between the role of perforin in viral clearance and immunopathology; perforin-deficient CD8 T cells were unable to clear the LCMV infection but were capable of causing immune-mediated damage. Finally, this study shows that perforin also plays a role in regulating T-cell-mediated autoimmunity. Mice that were deficient in both perforin and Fas exhibited a striking acceleration of the spontaneous lymphoproliferative disease seen in Fas-deficient (lpr) mice. Taken together, these results show that the perforin-mediated pathway is involved in downregulating T-cell responses during chronic viral infection and autoimmunity and that perforin and Fas act independently as negative regulators of activated T cells.

scholarly journals Fc-null anti-PD-1 monoclonal antibodies deliver optimal checkpoint blockade in diverse immune environments

2022 ◽  
Vol 10 (1) ◽  
pp. e003735
Author(s):  
Julia Moreno-Vicente ◽  
Jane E Willoughby ◽  
Martin C Taylor ◽  
Steven G Booth ◽  
Vikki L English ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Therapeutic Activity ◽  
Cell Responses

BackgroundDespite extensive clinical use, the mechanisms that lead to therapeutic resistance to anti-programmed cell-death (PD)-1 monoclonal antibodies (mAbs) remain elusive. Here, we sought to determine how interactions between the Fc region of anti-PD-1 mAbs and Fcγ receptors (FcγRs) affect therapeutic activity and how these are impacted by the immune environment.MethodsMouse and human anti-PD-1 mAbs with different Fc binding profiles were generated and characterized in vitro. The ability of these mAbs to elicit T-cell responses in vivo was first assessed in a vaccination setting using the model antigen ovalbumin. The antitumor activity of anti-PD-1 mAbs was investigated in the context of immune ‘hot’ MC38 versus ‘cold’ neuroblastoma tumor models, and flow cytometry performed to assess immune infiltration.ResultsEngagement of activating FcγRs by anti-PD-1 mAbs led to depletion of activated CD8 T cells in vitro and in vivo, abrogating therapeutic activity. Importantly, the extent of this Fc-mediated modulation was determined by the surrounding immune environment. Low FcγR-engaging mouse anti-PD-1 isotypes, which are frequently used as surrogates for human mAbs, were unable to expand ovalbumin-reactive CD8 T cells, in contrast to Fc-null mAbs. These results were recapitulated in mice expressing human FcγRs, in which clinically relevant hIgG4 anti-PD-1 led to reduced endogenous expansion of CD8 T cells compared with its engineered Fc-null counterpart. In the context of an immunologically ‘hot’ tumor however, both low-engaging and Fc-null mAbs induced long-term antitumor immunity in MC38-bearing mice. Finally, a similar anti-PD-1 isotype hierarchy was demonstrated in the less responsive ‘cold’ 9464D neuroblastoma model, where the most effective mAbs were able to delay tumor growth but could not induce long-term protection.ConclusionsOur data collectively support a critical role for Fc:FcγR interactions in inhibiting immune responses to both mouse and human anti-PD-1 mAbs, and highlight the context-dependent effect that anti-PD-1 mAb isotypes can have on T-cell responses. We propose that engineering of Fc-null anti-PD-1 mAbs would prevent FcγR-mediated resistance in vivo and allow maximal T-cell stimulation independent of the immunological environment.

scholarly journals Antiviral CD4 and CD8 T–cell memory: differences in the size of the response and activation requirements

2000 ◽  
Vol 355 (1395) ◽  
pp. 373-379 ◽  
Author(s):  
Jason K. Whitmire ◽  
Kaja Murali-Krishna ◽  
John Altman ◽  
Rafi Ahmed
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Expansion Phase ◽  
Lcmv Infection

Following acute lymphocytic choriomeningitis virus (LCMV) infection, there is a potent antiviral CD8 T–cell response that eliminates the infection. This initial CD8 T–cell response is followed by a period of memory during which elevated numbers of virus–specific CD8 T cells remain in the mouse. CD4 T cells are also activated after LCMV infection, but relatively less is known about the magnitude and duration of the CD4 response. In this study, we used intracellular staining for interferon–γ to measure both CD4 and CD8 responses in the same mice at the single cell level. After LCMV infection, there was an increase in the number of activated CD4 T cells and an associated increase in the number of virus–specific CD4 T cells. At the peak of this expansion phase, the frequency of virus–specific CD4 T cells was 1 in 20 (0.5–1.0 × 106 per spleen). Like the CD8 response, long–term CD4 memory could be found up to a year after the infection with frequencies of approximately 1 in 260 (0.5–1.5 × 105 per spleen). However, the magnitude of virus–specific CD8 T cells was greater than virus–specific CD4 T cells during all phases of the immune response (expansion, death, and memory). At day 8, there were 20– to 35–fold more virusspecific CD8 Tcells than CD4 Tcells. This initial difference in cell number lasted into the memory phase as there remained a ten– to 20–fold difference in the CD8 and CD4 responses. These results highlight the importance of the expansion phase in determining the size of the memory T–cell pool. In addition to the difference in the magnitude, the activation requirements of CD8 and CD4 T–cell responses were different: CD8 T responses were not affected by blockade of CD40– CD40 ligand interaction whereas CD4 responses were reduced 90%. So while there is long–term memory in both the CD8 and CD4 compartments, the rules regulating the activation of CD8 and CD4 T cells and the overall magnitude of the responses are different.

scholarly journals Long-Term Immunity to Trypanosoma cruzi in the Absence of Immunodominanttrans-Sialidase-Specific CD8+T Cells

2016 ◽  
Vol 84 (9) ◽  
pp. 2627-2638 ◽  
Author(s):  
Charles S. Rosenberg ◽  
Weibo Zhang ◽  
Juan M. Bustamante ◽  
Rick L. Tarleton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Trypanosoma Cruzi ◽  
T Cell Responses ◽  
Content Type ◽  
Cell Responses ◽  
Pathogen Control ◽  
Immunodominant Epitopes

Trypanosoma cruziinfection drives the expansion of remarkably focused CD8+T cell responses targeting epitopes encoded by varianttrans-sialidase (TS) genes. Infection of C57BL/6 mice withT. cruziresults in up to 40% of all CD8+T cells committed to recognition of the dominant TSKB20 and subdominant TSKB18 TS epitopes. However, despite this enormous response, these mice fail to clearT. cruziinfection and subsequently develop chronic disease. One possible reason for the failure to cureT. cruziinfection is that immunodomination by these TS-specific T cells may interfere with alternative CD8+T cell responses more capable of complete parasite elimination. To address this possibility, we created transgenic mice that are centrally tolerant to these immunodominant epitopes. Mice expressing TSKB20, TSKB18, or both epitopes controlledT. cruziinfection and developed effector CD8+T cells that maintained an activated phenotype. Memory CD8+T cells from drug-cured TSKB-transgenic mice rapidly responded to secondaryT. cruziinfection. In the absence of the response to TSKB20 and TSKB18, immunodominance did not shift to other known subdominant epitopes despite the capacity of these mice to expand epitope-specific T cells specific for the model antigen ovalbumin expressed by engineered parasites. Thus, CD8+T cell responses tightly and robustly focused on a few epitopes within variant TS antigens appear to neither contribute to, nor detract from, the ability to controlT. cruziinfection. These data also indicate that the relative position of an epitope within a CD8+immunodominance hierarchy does not predict its importance in pathogen control.

scholarly journals Protection against Vaccinia Virus Challenge by CD8 Memory T Cells Resolved by Molecular Mimicry

2006 ◽  
Vol 81 (2) ◽  
pp. 934-944 ◽  
Author(s):  
Markus Cornberg ◽  
Brian S. Sheridan ◽  
Frances M. Saccoccio ◽  
Michael A. Brehm ◽  
Liisa K. Selin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Molecular Mimicry ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Epitopes ◽  
Cell Responses

ABSTRACT Live vaccinia virus (VV) vaccination has been highly successful in eradicating smallpox. However, the mechanisms of immunity involved in mediating this protective effect are still poorly understood, and the roles of CD8 T-cell responses in primary and secondary VV infections are not clearly identified. By applying the concept of molecular mimicry to identify potential CD8 T-cell epitopes that stimulate cross-reactive T cells specific to lymphocytic choriomeningitis virus (LCMV) and VV, we identified after screening only 115 peptides two VV-specific immunogenic epitopes that mediated protective immunity against VV. An immunodominant epitope, VV-e7r130, did not generate cross-reactive T-cell responses to LCMV, and a subdominant epitope, VV-a11r198, did generate cross-reactive responses to LCMV. Infection with VV induced strong epitope-specific responses which were stable into long-term memory and peaked at the time virus was cleared, consistent with CD8 T cells assisting in the control of VV. Two different approaches, direct adoptive transfer of VV-e7r-specific CD8 T cells and prior immunization with a VV-e7r-expressing ubiquitinated minigene, demonstrated that memory CD8 T cells alone could play a significant role in protective immunity against VV. These studies suggest that exploiting cross-reactive responses between viruses may be a useful tool to complement existing technology in predicting immunogenic epitopes to large viruses, such as VV, leading to a better understanding of the role CD8 T cells play during these viral infections.

scholarly journals Adrenergic signaling controls early transcriptional programs during CD8+ T cell responses to viral infection

2021 ◽  
Author(s):  
Leonardo Estrada ◽  
Didem Agac Cobanoglu ◽  
Aaron Wise ◽  
Robert Maples ◽  
Murat Can Cobanoglu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Receptor Activation ◽  
Cell Development ◽  
Primary Response ◽  
Cell Responses

Viral infections drive the expansion and differentiation of responding CD8+ T cells into variegated populations of cytolytic effector and memory cells. While pro-inflammatory cytokines and cell surface immune receptors play a key role in guiding T cell responses to infection, T cells are also markedly influenced by neurotransmitters. Norepinephrine is a key sympathetic neurotransmitter, which acts to suppress CD8 + T cell cytokine secretion and lytic activity by signaling through the beta2-adrenergic receptor (ADRB2). Although ADRB2 signaling is considered generally immunosuppressive, its role in regulating differentiation of effector T cells in response to infection has not been investigated. Using an adoptive transfer approach, we compared the expansion and differentiation of wild type (WT) to Adrb2-/- CD8 + T cells throughout the primary response to vesicular stomatitis virus (VSV) infection in vivo. We measured the dynamic changes in transcriptome profiles of antigen-specific CD8 + T cells as they responded to VSV. Within the first 7 days of infection, WT cells out-paced the expansion of Adrb2-/- cells, which correlated with reduced expression of IL-2 and the IL-2Ralpha; in the absence of ADRB2. RNASeq analysis identified over 300 differentially expressed genes that were both temporally regulated following infection and selectively regulated in WT vs Adrb2-/- cells. These genes contributed to major transcriptional pathways including cytokine receptor activation, signaling in cancer, immune deficiency, and neurotransmitter pathways. By parsing genes within groups that were either induced or repressed over time in response to infection, we identified three main branches of genes that were differentially regulated by the ADRB2. These gene sets were predicted to be regulated by specific transcription factors involved in effector T cell development, such as Tbx21 and Eomes. Collectively, these data demonstrate a significant role for ADRB2 signaling in regulating key transcriptional pathways during CD8 + T cells responses to infection that may dramatically impact their functional capabilities and downstream memory cell development.

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