Regulation of Anti-Viral Cd8+ T Cell Responses by the Pd-1 Pathway

PD-1 and its ligands, PD-L1 and PD-L2, constitute a critical immunoregulatory pathway for modulating CD8+ T cell responses. This pathway has become an important therapeutic target in cancer and chronic viral infections, where blockade of PD-1/PD-L1 reverses CD8+ T cell exhaustion and improves outcomes. However, it remains unclear how PD-1 pathway signals shape the development and maintenance of memory CD8+ T cell responses following acutely-resolved infection or exhausted CD8+ T cell responses following chronic infection. Absence of PD-1 results in early over-activation, excessive proliferation and diminished survival of virus-specific CD8+ T cells during both acutely-resolved and chronic viral infections. Following influenza infection, PD-1 pathway deficiency led to sub-optimal CD8+ T cell memory development. Defects were observed in the magnitude of the influenza-specific CD8+ T cell responses, as well as in cytokine production and recall capacity. Similarly, during chronic LCMV infection, PD-1 deficient CD8+ T cells were more dysfunctional than their WT counterparts. Permanent absence of PD-1 dramatically dysregulated lineage dynamics and long-term stability of exhausted CD8+ T cell populations through a mechanism involving the transcription factors T-bet and Eomesodermin. As a result, PD-1 deficiency led to the accumulation of terminally-differentiated, but more cytotoxic, exhausted CD8+ T cells. These findings reveal a novel dual role for PD-1 signals during acutely-resolved and chronic viral infections. PD-1 pathway signals clearly restrict CD8+ T cell activation, expansion and function early, consistent with previous work. However, in doing this, PD-1 also preserves the quantity and quality of long-term memory or exhausted CD8+ T cell responses. Thus, PD-1 acts as a critical rheostat on CD8+ T cells, balancing the need for activation to achieve pathogen clearance with the establishment and maintenance of long-term memory or exhausted T cell responses

The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells

The transcription factor BATF is required for interleukin 17 (IL-17)-producing helper T cell (TH17) and follicular helper T cell (TFH) differentiation. Here, we show that BATF also has a fundamental role in regulating effector CD8+ T cell differentiation. BATF-deficient CD8+ T cells show profound defects in effector expansion and undergo proliferative and metabolic catastrophe early after antigen encounter. BATF, together with IRF4 and Jun proteins, binds to and promotes early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors, while paradoxically repressing genes encoding effector molecules (IFN-γ and granzyme B). Thus, BATF amplifies TCR-dependent transcription factor expression and augments inflammatory signal propagation but restrains effector gene expression. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved

The inositol phosphatase MTMR4 is a novel target of the ubiquitin ligase Nedd4

The inositol phosphatase, MTMR4 (myotubularin-related protein 4), was identified as a novel interactor of the ubiquitin ligase Nedd4 (neural-precursor-cell-expressed developmentally down-regulated 4). hMTMR4 (human MTMR4) and Nedd4 co-immunoprecipitated and co-localized to late endosomes. The PY (Pro-Tyr) motif of hMTMR4 binds to WW (Trp-Trp) domains of hNedd4. MTMR4 expression was decreased in atrophying muscle, whereas Nedd4 expression was increased and hMTMR4 was ubiquitinated by hNedd4, suggesting that this novel interaction may underlie the biological process of muscle breakdown

Sex Disparity in Cord Blood FoxP3+ CD4 T Regulatory Cells in Infants Exposed to Malaria In Utero.

Sex differences in the immune response and in infectious disease susceptibility have been well described, although the mechanisms underlying these differences remain incompletely understood. We evaluated the frequency of cord blood CD4 T cell subsets in a highly malaria-exposed birth cohort of mother-infant pairs in Uganda by sex. We found that frequencies of cord blood regulatory T cell ([Treg] CD4+CD25+FoxP3+CD127lo/-) differed by infant sex, with significantly lower frequencies of Tregs in female than in male neonates (P = .006). When stratified by in utero malaria exposure status, this difference was observed in the exposed, but not in the unexposed infants

The interferon paradox: can inhibiting an antiviral mechanism advance an HIV cure?

While antiretroviral therapy (ART) has improved the quality of life and increased the life span of many HIV-infected individuals, this therapeutic strategy has several limitations, including a lack of efficacy in fully restoring immune function and a requirement for life-long treatment. Two studies in this issue of the JCI use a humanized mouse model and demonstrate that type I interferon (IFN) is induced early during HIV infection and that type I IFN–associated gene signatures persist, even during ART. Importantly, blockade of type I IFN improved immune function, reduced the HIV reservoir, and caused a delay in viral rebound after ART interruption. Together, these two studies support further evaluation of IFN blockade as a supplement to ART

Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells

Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8+ T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established “exhausted” CD8+ T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8+ T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8+ TEX cells. These results demonstrate that CD8+ T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation