It is demonstrated that PD-1 inhibition enhances CD4+ T cell function, specifically through increased IL-21 production from T follicular helper (Tfh) cells which promotes both humoral and cytotoxic antiviral responses.
Abstract
T cell exhaustion, a defining hallmark of chronic viral infections and cancer, is characterized by the progressive loss of effector function and sustained expression of inhibitory receptors on T cells. Although immune checkpoint blockade (ICB) therapies, such as PD-1 inhibition, can transiently reinvigorate subsets of exhausted CD8+ T cells, their efficacy remains constrained by the limited pool of self-renewing, progenitor-like TCF1+ CXCR5+ CD8+ T cells. We have previously demonstrated that B cell—derived IL-27 signaling is necessary for the expansion and maintenance of this progenitor-like population during chronic infection. Using an IL-27 receptor deficient mouse model, we reveal a previously unrecognized mechanism by which PD-1 blockade mediates viral clearance. We demonstrate that PD-1 inhibition enhances CD4+ T cell function, specifically through increased IL-21 production from T follicular helper (Tfh) cells which promotes both humoral and cytotoxic antiviral responses. Our findings identify a novel IL-27 independent CD4+ T cell axis through which checkpoint blockade controls persistent viremia.
To determine the impact of checkpoint inhibition on persistent viral infection, IL-27 receptor—deficient mice were infected with chronic lymphocytic choriomeningitis virus (LCMV clone 13) and treated with PD-1 blocking antibodies. We used flow cytometry and viral titers to evaluate CD4+ and CD8+ T cell subsets, the importance of IL-21, and persistent viral clearance.
PD-1 blockade restored antiviral immunity in IL-27 receptor—deficient mice and resulted in enhanced CD4+ T cell function. We saw increased IL-21 production from T follicular helper cells that led to higher cytotoxic and humoral antiviral responses.
Our studies reveal that PD-1 blockade can drive persistent viral clearance through an IL-27—independent mechanism that involves IL-21—producing CD4+ T cells.
N/A
Viral Immunology (VIR)
T cell exhaustion, a defining hallmark of chronic viral infections and cancer, is characterized by the progressive loss of effector function and sustained expression of inhibitory receptors. Although immune checkpoint blockade (ICB) therapies, such as PD-1 inhibition, can transiently reinvigorate exhausted CD8+ T cell subsets, their efficacy is limited by the small pool of self-renewing, progenitor-like TCF1+ CXCR5+ CD8+ T cells. We previously demonstrated that B cell—derived IL-27 signaling is required for the expansion of this progenitor-like population during chronic infection. Using an IL-27 receptor—deficient mouse model, we uncover a previously unrecognized mechanism by which PD-1 inhibition mediates viral clearance and enhanced humoral responses.
IL-27 receptor—deficient mice were infected with LCMV clone 13 and treated with PD-1—blocking antibodies at later stages post-infection. Following completion of antibody treatment, immune responses were analyzed using flow cytometry to characterize T cell and B cell subsets. Antiviral antibody responses and viral clearance were evaluated using serological assays, sequencing approaches, and focus-forming assay.
PD-1 inhibition promoted viral clearance during the persistent phase without inducing the immunopathology typically observed with early anti—PD-1 treatment. This was associated with increased IL-21 production by T follicular helper (Tfh) cells, leading to augmented cytotoxic and humoral antiviral responses.
Our findings reveal a previously unrecognized and novel, IL-27—independent CD4+ T cell axis through which PD-1 checkpoint blockade restores antiviral immunity during persistent viral infection. These results redefine the mechanistic landscape of checkpoint immunotherapy, highlighting CD4+ T cells as critical effectors in controlling persistent viral infections.
N/A
Immune Response Regulation: Cellular Mechanisms (IRC)
Prajakta Warang, J. Teijaro· Journal of Immunology· 0 citations
Cytotoxic CD8 T cells play a crucial role in eliminating infections and cancer. However, chronic antigen exposure induces their development into exhausted T (TEX) cells. TEX cells exhibit increased inhibitory receptors or checkpoints expression, defective effector functions and thus unable to eliminate the virus-infected cells and cancers. Antibodies inhibiting signaling through checkpoints PD1 or CTLA4 (immune checkpoint blockade or ICB) induce differentiation of TEX cells into effectors that eliminate cancer and viral infected cells. PD1 blockade is the leading ICB against several tumor types. However, > 50% of the cancer patients either do not respond or get durable benefits from PD1 blockade. Therefore, there is an urgent need to understand the PD1-independent mechanism to improve immunotherapy against tumors resistant to PD1 blockade.
In order to address the role of UFL-1 in CD8 T cell exhaustion, we used LCMV acute and chronic infection models in control and CD4 specific UFL-1 knockout mice. Different subset of CD8 T cells and their differentiation status and functional response upon activation were analyzed using flow cytometry and ScRNA-seq.
Acute exposure to antigens, is not known to cause T cell exhaustion. We found that UFL1-deficient CD8 T cells undergo exhaustion during acute viral infection. During chronic antigen presence, such as in tumor models and chronic viral infections, UFL1 deficiency worsens CD8 T cell exhaustion. Additionally, the PD1 blockade fails to improve the functionality of UFL1-deficient TEX cells. Consistent with this, UFL1 expression in tumor-infiltrating CD8 T cells is positively correlated with the progression-free survival of melanoma patients treated with PD1 blockade.
These findings suggest that exhaustion in UFL1-deficient CD8 T cells is PD1-independent. Therefore, understanding how UFL1 prevents T cell exhaustion would help discover new ways to improve immunotherapies, especially for cancers that do not respond to PD1 blockade.
NIH Funding - NIAID00054
Immune Response Regulation: Molecular Mechanisms (IRM)
Aravind Rathakrishnan, Nagendra Singh, Francis Anazodo et al.· Journal of Immunology· 0 citations
The establishment of immunological memory is crucial for durable antiviral immunity and underlies effective vaccine design in enhancing memory responses. The retinoic acid receptor—related orphan receptor α(RORα), a ligand-regulated transcription factor of the nuclear receptor superfamily, has been implicated in CD8+ T cell immunity, yet its role remains poorly defined.
To investigate this, we integrated genomic approaches with both genetic and pharmacologic perturbations of RORα to examine its role in CD8+ T cell development during antiviral responses.
RORα-deficient mice infected with acute lymphocytic choriomeningitis virus (LCMV) exhibited fewer virus-specific CD8+ T cells and higher splenic viral titers at day 5 post-infection than wild-type controls. Despite reduced numbers, RORα-deficient CD8+ T cells showed enhanced cytotoxic potential, indicating that RORα modulates effector programming rather than overall functional capacity. RORα deficiency also led to increased migration and redistribution of CD8+ T cells into non-lymphoid compartments, particularly the liver and adipose tissues, and promoted the development of memory precursors (MP), peripheral memory (TPM), and tissue-resident memory (TRM) populations. Single-cell RNA-seq and ATAC-seq revealed enrichment of transcriptional and chromatin programs linked to MP and TRM gene signatures, including elevated expression of Tcf7 and Runx family members, alongside reduced accessibility at loci governing terminal effector differentiation. Pharmacologic inhibition of RORα with the RORα-selective inverse agonist, SR3335, recapitulated the knockout phenotype, favoring memory CD8+ T cell differentiation over terminal effectors.
Collectively, our data reveal distinct programming of CD8 T effector versus memory populations attributable to RORα activity. As a ligand-regulated transcription factor, RORα may be a promising target to enhance CD8+ T cell memory responses for improved vaccines and cell-based immunotherapies.
N/A
Immune Response Regulation: Molecular Mechanisms (IRM)
Jonathan Chuck, Sean Campbell, Anna Schell et al.· Journal of Immunology· 0 citations
Classically CD4+ T cells are recognized for their helper functions in coordinating adaptive immunity; however recent studies have identified a unique subset of antigen experienced CD4+ T cells which acquire cytotoxic potential evidenced by their ability to eliminate MHC II+ targets in vivo. Though these cytotoxic CD4+ T cells (CD4 CTLs) play a crucial role in various chronic viral infections and cancers, the regulation of their function and in vivo target specificity remain unclear.
To study CD4 CTL dynamics, we used a well established mice model of acute (Armstrong) and chronic (Clone 13) LCMV infection.
We demonstrate that both acute and chronic LCMV infections rapidly induce a subset of granzyme B and perforin-expressing Th1 cells with in vivo cytotoxic function. These cells are detectable as early as 48 hrs post-infection, and their killing activity is in part perforin-dependent. Intriguingly, in contrast to the sustained cytotoxic activity seen in acute infection, chronic infection triggers a progressive decline in CD4 CTL killing ability in vivo, that is restored upon PD-L1 blockade. The early killing activity suggested that these cells might regulate antigen presentation during infection. Using a 1:1 Wildtype:MHC II-/- bone marrow chimera model we show that MHC II-/- DCs (which are immune to CD4 CTL killing but susceptible to CD8 T cell and NK cell killing) undergo initial immune-mediated killing similar to WT DCs by 60 hours post LCMV-infection. However, by Day 9 of chronic LCMV infection a higher proportion of MHC II-/- CD8α+ DCs were LCMV-infected compared to wildtype CD8α+ DCs in the same mice, suggesting that CD4 CTLs play a role in limiting viral infection in this specific DC subset during chronic viral infection.
In conclusion, our study provides new insights into the dynamics of CD4 CTLs during acute and chronic viral infections, and begins to define their specific target cells in vivo.
Showalter Trust Foundation award, the Indiana CTSI and funds from IUSCCC and IU CCEH
Viral Immunology (VIR)
Prakash Sahoo, Chamese K. Brewer, Laura M. Snell· Journal of Immunology· 0 citations
CD8 T cells are critical players in immune responses against pathogens. Interleukin-21 (IL-21) is predominantly produced by CD4 T cells and exerts multifaceted effects on CD8 T cell regulation and function. Using Il21-reporter and Il21-fate mapping mice, we report that a subpopulation of activated CD8 T cells also produces IL-21 in the context of lymphocytic choriomeningitis virus (LCMV) infection. During the early effector phase of both acute and chronic infections, IL-21-expressing CD8 T cells exhibit substantial proliferative and cytotoxic capacities, with higher levels of interferon-γ (IFN-γ) and granzyme B (GZMB) compared with IL-21- counterparts. Moreover, CD8 T cell-derived IL-21 played a critical protective role in chronic, but not acute, infection. IL-21 expression in CD8 T cells appeared to be largely restricted to exhausted progenitor T cells during the exhaustion phase of chronic infection. These findings identify IL-21-expressing CD8 T cells as pivotal players in the control of chronic infection.
Zixuan Zhao, Han Feng, Xiaohong Zhao et al.· Science immunology· 0 citations
RvD5 reduced PD-1 expression on T cells and PD-L1 expression on cancer cells, thereby restoring T cell antitumor functions by delaying their differentiation into Tex, and suppresses tumor growth by dampening inflammation and delaying T cell exhaustion within the TME.
Maria Tredicine, Simona D'Orazio, Nunzia Coletta et al.· Journal of Immunology· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
