UCSF

Adaptive immune responses are essential for long-term immunity and the success of many disease treatments such as vaccines and antibody-based immunotherapy. Conventional type I dendritic cells (cDC1s) initiate this response by presenting antigen, providing co-stimulation, and producing cytokines to prime de novo T cell responses. After priming, T cells clonally expand, create long-term memory, and execute effector functions to clear tumors and pathogens. Understanding signals that can affect T cell priming and expansion in disease is vital for improving treatment approaches. This study explores how tumors can disrupt cDC1-T cell priming distal to the tumor site by using an intravenous Listeria monocytogenes infection as a model of a peripheral Type-I immune response. In vivo studies revealed a tumor-initiated IL-1 autocrine loop drives cDC1 dysfunction in the spleen, and blockade of IL-1R signaling was sufficient to rescue deficits in CD8+ T cell priming abilities of cDC1s. Further, we developed a CyTOF approach to investigate T cell dynamics after key priming timepoints. We performed a comparative analysis of T cell receptor (TCR) Vα- and Vβ-chain use among different diseases and treatment modalities. This strategy identified expansions of specific Vβ and Vα chain-expressing CD8+ and CD4+ T cells with varying differentiation states in response to Listeria monocytogenes, tumors, and respiratory influenza infection. Taken together, these studies advance our understanding of T cell priming and differentiation dynamics by investigating signals upstream of cDC1 activation as well as T cell TCR use and differentiation across disease.