Role of HIV Envelope Proteins In Viral Replication and HIV Pathogenesis

National Institute Of Allergy And Infectious Diseases

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Abstract

We cultured naïve CD4+ T cells under conditions that mimicked mucosal environments. This included signaling through MAdCAM-1 in the presence of Retinoic Acid (RA) and TGF-β. Our results demonstrate that IL-6 plays a key role in the induction of TRM-associated markers, including CD69, CD103 and CCR5. The combination of MAdCAM-1 and TGF-β potently induced TRM markers despite low level proliferation. Other factors that signal through JAK/STAT also contributed to TRM differentiation, and antagonists that inhibit JAK/STAT signaling pathways suppressed MAdCAM-1 mediated TRM cells formation. Our findings revealed that IL-6 is a pivotal cytokine in the generation of tissue-resident CD4+ T cells and showed that MAdCAM-1 works together with TGF-β, RA and IL-6 in this process. We also tested the ability of MAdCAM-1 to induce the differentiation of primary CD8+ cells into TRM. HIV-specific CD8+ TRM are present in HIV persistent sites such as gut tissues and lymph node and participate in immune surveillance and are correlated with HIV protection. Understanding the mechanisms involved in inducing CD8+ TRM will inform the development of anti-HIV-1 immune-based therapies and vaccines targeted to the mucosa. We developed a new method to induce freshly isolated CD8+ T cells to differentiate into multiple types of TRMs by stimulating primary CD8+ T cells with MAdCAM-1, VCAM-1 and anti-CD28 in the presence of retinoic acid (RA) and TGF-beta.