Targeting TIM-3 to reverse immune exhaustion during chronic viral infection Open Access

Tieu, Roger (2015)

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Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) have emerged as a major threat by being able to impair the immune system. Though the exact mechanism of disease pathogenesis is not clear, several inhibitory receptors involved in effector mechanisms are invoked by the chronic HIV infection leading to limited antiviral response. TIM-3 (T cell immunoglobulin and mucin domain 3) has been identified as an important albeit still understudied negative regulatory of immunity. In order to characterize TIM-3 in the context of chronic viral infection, we used SIV-infected rhesus macaques as our model system. We find there is a similar frequency of TIM-3 expressing dendritic cells (DCs) between humans and rhesus macaques. Further characterization of TIM-3 expressing DCs revealed they represent an activated population with increased CD86 expression and secreted tumor necrosis factor alpha (TNF-alpha) in response to the presence of dsRNA (double stranded RNA). We also find an increased concentration of soluble galectin-9, a TIM-3 ligand, in plasma samples after SIV infection. Staining for general TIM-3 ligands revealed their presence on various immune cell populations, including T cells, B cells, monocytes, and DCs. Finally, we created a fusion protein of extracellular TIM-3 and the Fc domain of an IgG2 antibody to generate TIM-3-Fc for blocking TIM-3 signaling. Treatment of peripheral blood mononuclear cells with TIM-3-Fc results in enhanced proliferation of antigen-specific CD4+ T cells in vitro. Overall, these findings reveal a need to further characterize TIM-3 since we establish TIM-3 as not only an inhibitory molecule for adaptive immunity, but also an activation molecule for innate immunity.

Table of Contents

Introduction 1

Objectives 10

Methods 11

Results 20

Discussion 40

Future Directions 45

Conclusion 46

References 47

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