Summary Chronic viruses and cancers thwart immune responses in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, P-selectin glycoprotein ligand-1 (PSGL-1) that is upregulated on responding T cells. PSGL-1-deficient mice cleared the virus due to increased intrinsic survival of multifunctional effector T cells that had downregulated PD-1 as well as other inhibitory receptors. Notably, this response resulted in CD4+ T cell-dependent immunopathology. Mechanistically, PSGL-1 ligation on exhausted CD8+ T cells inhibited T cell receptor (TCR) and interleukin-2 (IL-2) signaling, and upregulated PD-1, leading to diminished survival with TCR stimulation. In models of melanoma cancer where T cell dysfunction occurs, PSGL-1-deficiency led to PD-1 downregulation, improved T cell responses, and tumor control. Thus, PSGL-1 plays a fundamental role in balancing viral control and immunopathology, and also functions to regulate T cell responses in the tumor microenvironment.
Chronic viruses, including HIV and hepatitis B and C, can survive in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, P-selectin glycoprotein ligand-1 (PSGL-1) that is upregulated on responding T cells. PSGL-1-deficient mice unexpectedly cleared the virus due to dramatic increases in the intrinsic survival of multifunctional effector T cells that had downregulated PD-1 and other inhibitory receptors. Notably, this response resulted in immunopathology requiring CD4+ T cells. Mechanistically, PSGL-1 ligation on exhausted CD8+ T cells sustained PD-1 expression and diminished their survival during TCR stimulation. In a model of malignant melanoma where T cell dysfunction also occurs, PSGL-1 deficiency led to PD-1 downregulation, improved T cell responses and tumor control. Thus, PSGL-1 not only plays a fundamental role in balancing viral control and immunopathology, but also functions as a checkpoint that regulates T cell function in the tumor microenvironment.
During a chronic viral infection, inhibitory receptors play a crucial role in controlling viral persistence and T cell exhaustion. However, the role of homing molecules in this process has been poorly investigated. Using the chronic LCMV virus model, Clone 13, we found that expression of CD44, a cell surface glycoprotein broadly used to identify activated T cells, dampens antigen specific T cell responses. In CD44-deficient hosts, we observed a significant increase in antigen specific CD4 and CD8 T cells functions with decreased PD-1 expression and a striking increase in multiple cytokine production. T cell accumulation was not due to increased proliferation based on BrdU incorporation, and the increased CD8 T cell response required CD4 T cell help because CD8 T cell exhaustion was maintained in CD4 depleted CD44-deficient mice. Using a bone marrow chimera approach, we found that restricting the CD44 deficiency in the non-hematopoietic compartment was sufficient to reproduce the observations made in the complete CD44 deficient hosts. Finally CD44-deficiency resulted in viral clearance by d15pi. Importantly, treatment of WT mice with a CD44-blocking antibody increased antigen specific CD4 and CD8 T cell recovery and some aspects of T cell function as early as d9pi. Taken together, these results indicate that CD44 is a novel inhibitory receptor that can be targeted to improve T cell response during chronic viral infections.
The tumor microenvironment can promote tumor growth by suppressing effector T cell responses. Using a melanoma model that recapitulates aspects of human disease, we investigated the role of the adhesion molecule, P-selectin glycoprotein ligand-1 (PSGL-1) in tumor infiltrating lymphocytes (TILs). We found that PSGL-1 was highly expressed on TILs that also expressed high PD-1 and TIM-3 inhibitory receptors. PSGL-1-deficiency did not impact T cell recruitment in tumors but instead resulted in a greater TIL accumulation. Furthermore, PSGL-1-deficient T cells had reduced PD-1 expression and increased production of effector cytokines that resulted in delayed tumor growth. We did not find differences in Treg recruitment but instead had an increased effector to Treg ratio in tumors. Our findings show that PSGL-1 does not have a nonredundant role in the trafficking of TILs into melanoma tumors, but can act as an immune checkpoint inhibitor to limit anti-tumor T cell responses in the tumor microenvironment thereby promoting tumor growth.
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