Innate and adaptive lymphocytes instruct immune responses and regulate germinal center interactions in humans

Margaret Helen O'Connor

doi:10.17918/00000998

Within every human secondary lymphoid organ (SLO) there occurs a tightly regulated process to recognize and respond to antigens. The proper response to antigens is directed by germinal center (GC) formation which occurs in SLOs. Within a GC, a tightly regulated process occurs to ensure education of the adaptive immune cells to respond to antigen. Understanding the multiple adaptive and innate immunologic cell types required for the appropriate formation and resolution of the GC response is highly important to inform pathogenesis and treatment of diseases, and success of vaccines. The two critical cell types of the GC are GC T follicular helper (GC-Tfh) cells and their cognate GC B cells (GC-B) which upon interaction lead to creation of all aspects of humoral immunity. This process, once completed, must also be strategically resolved by mechanisms not yet fully understood. The central hypothesis of our work is that cells of both the innate and adaptive lymphocyte lineages are involved in modulating the function of the GC-Tfh cell and GC-B cell interaction, including a newly identified regulatory innate lymphoid cell (ILC), and thus impact humoral immunity. To test this hypothesis, first, we will explore the functions of innate immune cell subsets in the regulation of GC-Tfh/GC-B cell interaction and antibody responses. Specifically, we will determine the role of a new regulatory innate lymphoid cell (ILCFR) and innate lymphoid cell type 3 (ILC3) in modulating this interaction. Second, we will assess the function of an adaptive immune subset in the regulation of the GC-Tfh/GC-B cell interaction. This will be achieved by studying the function of CXCR5+CD8+ T cells. Lastly, we will explore the role of adenosine deaminase 1 (ADA-1) and its ability to enhance GC-Tfh cell functioning. All of these cell subsets have proven to have important and divergent roles in the formation, maintenance, and resolution of human GC interactions. We will also identify the mechanisms of actions of how these different cell types regulate GC interactions. This will be achieved by analyzing RNA transcriptional profiles of these cell types where we performed deep sequencing comparisons of multiple innate and adaptive human tonsillar cell types. We will also perform loss and gain of function studies to identify the molecular mechanisms and in vivo and in vitro studies. Overall, our work strongly demonstrates that GC-Tfh/GC-B cell interactions in SLOs, which dictate the fate of cell mediated and humoral immunity, can be negatively or positively impacted by innate and adaptive immune subsets. These opposing forces need to be tightly regulated. If GC-Tfh/GC-B cell functioning is left unchecked, this may lead to autoimmune disease, cancers, and the inability to respond to infections and vaccines.

Innate and adaptive lymphocytes instruct immune responses and regulate germinal center interactions in humans

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Innate and adaptive lymphocytes instruct immune responses and regulate germinal center interactions in humans

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