Acute and chronic viral infections result in the differentiation of effector and exhausted T cells with functional and phenotypic differences that dictate whether the infection is cleared or progresses to chronicity. High CD38 expression has been observed on CD8⁺ T cells across various viral infections and tumors in patients, suggesting an important regulatory function for CD38 on responding T cells. Here, we show that CD38 expression was increased and sustained on exhausted CD8⁺ T cells following chronic lymphocytic choriomeningitis virus (LCMV) infection, with lower levels observed on T cells from acute LCMV infection. We uncovered a cell-intrinsic role for CD38 expression in regulating the survival of effector and exhausted CD8⁺ T cells. We observed increased proliferation and function of Cd38^-/- CD8⁺ progenitor exhausted T cells compared to those of wild-type (WT) cells. Furthermore, decreased oxidative phosphorylation and glycolytic potential were observed in Cd38^-/- CD8⁺ T cells during chronic but not acute LCMV infection. Our studies reveal that CD38 has a dual cell-intrinsic function in CD8⁺ T cells, where it decreases proliferation and function yet supports their survival and metabolism. These findings show that CD38 is not only a marker of T cell activation but also has regulatory functions on effector and exhausted CD8⁺ T cells. IMPORTANCE Our study shows how CD38 expression is regulated on CD8⁺ T cells responding during acute and chronic viral infection. We observed higher CD38 levels on CD8⁺ T cells during chronic viral infection compared to levels during acute viral infection. Deleting CD38 had an important cell-intrinsic function in ensuring the survival of virus-specific CD8⁺ T cells throughout the course of viral infection. We found defective metabolism in Cd38^-/- CD8⁺ T cells arising during chronic infection and changes in their progenitor T cell phenotype. Our studies revealed a dual cell-intrinsic role for CD38 in limiting proliferation and granzyme B production in virus-specific exhausted T cells while also promoting their survival. These data highlight new avenues for research into the mechanisms through which CD38 regulates the survival and metabolism of CD8⁺ T cell responses to viral infections.

Immune-checkpoint inhibitors have had impressive efficacy in some patients with cancer, reinvigorating long-term durable immune responses against tumors. Despite the clinical success of these therapies, most patients with cancer continue to be unresponsive to these treatments, highlighting the need for novel therapeutic options. Although P-selectin glycoprotein ligand-1 (PSGL-1) has been shown to inhibit immune responses in a variety of disease models, previous work has yet to address whether PSGL-1 can be targeted therapeutically to promote antitumor immunity. Using an aggressive melanoma tumor model, we targeted PSGL-1 in tumor-bearing mice and found increased effector CD4+ and CD8+ T-cell responses and decreased regulatory T cells (Treg) in tumors. T cells exhibited increased effector function, activation, and proliferation, which delayed tumor growth in mice after anti-PSGL-1 treatment. Targeting PD-1 in PSGL-1-deficient, tumor-bearing mice led to an increased frequency of mice with complete tumor eradication. Targeting both PSGL-1 and PD-1 in wild-type tumor-bearing mice also showed enhanced antitumor immunity and slowed melanoma tumor growth. Our findings showed that therapeutically targeting the PSGL-1 immune checkpoint can reinvigorate antitumor immunity and suggest that targeting PSGL-1 may represent a new therapeutic strategy for cancer treatment.

Chronic infections and cancers evade the host immune system through mechanisms that induce T cell exhaustion. The heterogeneity within the exhausted CD8⁺ T cell pool has revealed the importance of stem-like progenitor (Tpex) and terminal (Tex) exhausted T cells, although the mechanisms underlying their development are not fully known. Here we report High Mobility Group Box 2 (HMGB2) protein expression is upregulated and sustained in exhausted CD8⁺ T cells, and HMGB2 expression is critical for their differentiation. Through epigenetic and transcriptional programming, we identify HMGB2 as a cell-intrinsic regulator of the differentiation and maintenance of Tpex cells during chronic viral infection and in tumors. Despite Hmgb2^-/- CD8⁺ T cells expressing TCF-1 and TOX, these master regulators were unable to sustain Tpex differentiation and long-term survival during persistent antigen. Furthermore, HMGB2 also had a cell-intrinsic function in the differentiation and function of memory CD8⁺ T cells after acute viral infection. Our findings show that HMGB2 is a key regulator of CD8⁺ T cells and may be an important molecular target for future T cell-based immunotherapies.