TRAF3 shapes CD4 T cell fate and function during chronic infection - PROJECT SUMMARY Chronic infections caused by persistent viruses or parasites impose a significant burden on human health and healthcare systems. These infections disrupt immune responses, often leading to T cell dysfunction, immune exhaustion, and loss of T cell memory potential. CD4+ T cells are central to immune defense against chronic infections, yet their differentiation and functional responses differ significantly from those in acute infections. During chronic infection, CD4+ T cells exhibit reduced pro-inflammatory cytokine production, increased expression of immunoregulatory molecules, and functional adaptations such as the differentiation of T follicular helper (TFH) cell, which produce IL-10 and IL-21 production to support germinal center B cell responses and humoral immunity. Despite progress in understanding TFH and T helper type 1 (TH1) cell differentiation, the molecular mechanisms regulating CD4+ T cell fate during chronic infections remain poorly defined. We recently identified tumor necrosis factor receptor-associated factor 3 (TRAF3) as a key regulator of TFH differentiation during acute infection. Our preliminary data indicate that TRAF3 modulates TFH cell fate by regulating cytokine responsiveness, lineage- specific transcription factors like BCL6, and chromatin accessibility at key TFH and TH1 lineage gene loci. Notably, we also observed nuclear localization of TRAF3, suggesting a previously unrecognized role in transcriptional and epigenetic regulation. This proposal employs technically innovative and high-resolution approaches, leveraging complementary experimental systems of chronic infection and robust single-cell technologies to dissect how TRAF3 integrates T cell receptor, cytokine, and co-stimulatory signals to regulate TFH, TH1, and memory-like CD4+ T cell differentiation. Using cutting-edge genomic and epigenetic approaches, including single-cell RNA sequencing (scRNA-seq), ATAC-seq, CRISPR/Cas9-mediated gene editing, and retroviral-mediated genetic manipulation, we will define how TRAF3 orchestrates transcriptional programs, chromatin accessibility and nuclear regulatory network to fine-tune immune responses. Given TRAF3’s implication in autoimmune disorders and malignancies, uncovering its role in chronic infection may inform new therapeutic strategies to modulate T cell responses in infection, vaccination, and autoimmunity. By linking TRAF3’s cytoplasmic signaling functions with its nuclear roles, this study aims to provide conceptual advances that could pave the way for novel strategies to enhance immunity and control inflammation in human health.
