Thursday, April 3, 2025
4/3/2025
Mechanisms of CD8+ T cell-induced Innate Immune Activation - PROJECT SUMMARY CD8+ T cells play a pivotal role in protective immune responses against intracellular pathogens and cancer progression. Most CD8+ T cells activated during a primary immune response will contract and die, however, a small percentage will persist and form long-lived memory populations (CD8+ Tmem). CD8+ Tmem can occupy various anatomical niches and rapidly respond to subsequent antigen encounters, leading to effective secondary responses. Despite the importance of cytotoxic functions, much work has shed light on the ability of CD8+ T cells to confer protection from pathogens in the absence of cytotoxic machinery. However, the underlying mechanisms responsible for such protection remain ill-defined. Our lab has demonstrated that memory CD4+ T cells are able to engage innate immune cells and drive inflammatory responses, a process dependent on MHC-TCR and Tumor Necrosis Factor Superfamily (TNFSF) ligand-receptor interactions. Here, ligands expressed by memory CD4+ T cells engage receptors on myeloid cells, leading to NFκB-dependent cytokine production. We have generated preliminary data suggesting that CD8+ Tmem, but not effector CD8+ T cells, can also activate myeloid proinflammatory responses during cognate interactions, albeit through distinct mechanisms from those of memory CD4+ T cells. CD8+ T cell-induced myeloid proinflammatory responses result in production of several key innate cytokines, including IL-1β and IL-6, both of which are critical to anti-microbial responses. Additionally, antigen-presenting cells cultured with CD8+ Tmem display increased transcript levels of Type I Interferons (IFN) and Interferon-Stimulated Genes (ISGs), both of which are critical to antiviral and anti-cancer responses. Similar increases in ISG responses were also observed in vivo within various tissues after selective reactivation of CD8+ Tmem. These data suggest an evolutionary mechanism wherein reactivation of CD8+ Tmem results not only in rapid effector function and cell killing, but also innate activation and induction of a systemic anti-microbial response. The objective of this proposal is to test the overall hypothesis that induction of innate inflammation is a critical, non-canonical function of CD8+ Tmem necessary for optimal immune responses. In Aim 1, we plan to discern the molecular mechanisms underlying CD8+ Tmem-induced innate inflammatory responses and the importance of this axis in microbial immunity. We will identify key ligand-receptor interactions necessary for proinflammatory cytokine production and initiation of Type I IFN responses. In Aim 2, we will investigate the mechanisms that promote or attenuate CD8+ T cell-induced innate responses, particularly focusing on the role of immune checkpoint molecule signaling during cognate interactions. Successful completion of these aims will uncover a novel function of CD8+ T cells in modulation of innate inflammatory responses, with profound implications for therapeutic development.
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