Browsing by Subject "CD8 T cells"

Now showing 1 - 3 of 3
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    Expansive residence decentralizes immune homeostasis
    (2020-10) Wijeyesinghe, Sathi
    Metazoans relegate specific tasks to dedicated organs that are established early in development, occupy discrete anatomic locations, and typically remain fixed in size. The adult immune system arises from a centralized hematopoietic niche that maintains self-renewing potential, and upon maturation, becomes distributed throughout the body to monitor environmental perturbations, regulate tissue homeostasis, and mediate organism-wide defense. This study examines how immunity is integrated within adult mouse tissues while addressing issues of durability, expansibility, and contribution to organ cellularity. Focusing on antiviral T cell immunity, we observe durable maintenance of resident memory T cells (TRM) up to 450 days after infection. Once established, resident T cells did not require the T cell receptor for survival or retention of a poised effector-like state. While resident memory indefinitely dominated most mucosal organs, surgical separation of parabiotic mice unexpectedly revealed a tissue-resident provenance for bloodborne memory T cells, and circulating memory slowly made substantial contributions to tissue immunity in some organs. Following additional microbial experiences via serial immunizations or pet shop mice co-housing, we find tissue pliancy allows for the accretion of tissue-resident memory, without axiomatic erosion of preexisting antiviral T cell immunity. Extending these findings, we demonstrate tissue residence and organ pliancy are generalizable aspects underlying the homeostasis of innate and adaptive immunity. The immune system-at-large grows commensurate to microbial experience reaching up to 25% of visceral organ cellularity. Regardless of location, many white blood cell populations adopted a tissue residency program within nonlymphoid organs. Thus, residence, rather than renewal or recirculation, typifies nonlymphoid immune surveillance, and organs serve as a pliant storage reservoir that can accommodate the continuous expansion of the cellular immune system throughout life. While hematopoiesis (‘to make blood’) restores certain elements of the immune system, in parallel, nonlymphoid organs sustain an accrual of durable tissue-autonomous cellular immunity, resulting in the progressive decentralization of organismal immune homeostasis.
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    The function and utility of self-specific CD8 T cells
    (2018-02) Nelson, Christine
    Self-specific CD8 T cells have the potential to provide great benefit, but also to cause great harm. This thesis research seeks to uncover the mechanisms controlling CD8 T cell tolerance to self and tumor antigens. We show that the induction of CD8 T cell tolerance is dependent on inhibitory receptor signaling, but the maintenance of tolerance is not. Thus, only newly primed self-specific CD8 T cell are amenable to immune checkpoint blockade activation. We establish CD8 T cell tolerance as an active state of differentiation that is dependent on suppressed antigen-sensing. We demonstrate that robust stimulation with self-antigen and inflammation induces avidity maturation of the self-specific CD8 T cell repertoire, which serves to renew susceptibility to immune checkpoint and aid in anti-tumor responses. We validate that endogenous self-specific CD8 T cells exist within the immune repertoire and can expanded by similar vaccination methods. Expanded self-specific CD8 T cells generate tissue resident memory in non-lymphoid tissues and secondary lymphoid organs, that are phenotypically distinct from non-self-specific populations. Finally, we show that self-specific CD8 T cells synergize with tumor neo-antigen specific CD8 T cells in the treatment and prevention of cancer. This data provides significant insight into the requirements for the induction of self and anti-tumor T cell responses.
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    Regulation of CD8 T cell memory by ADAP
    (2014-12) Fiege, Jessica
    During acute infections, naïve antigen-specific CD8 T cells are activated and differentiate into effector T cells, the majority of which undergo contraction after pathogen clearance. A small population of CD8 T cells survives the contraction phase and persists as memory, to protect against future infections. Memory CD8 T cells are heterogeneous and can be found in secondary lymphoid organs (SLOs), blood and non-lymphoid tissues (NLTs). Here I demonstrate the adaptor protein ADAP enhances the formation of memory CD8 T cells in both SLOs and NLTs after pathogen challenge. ADAP-deficient memory CD8 T cells in SLOs proliferate robustly to a systemic secondary challenge. Additionally, ADAP-deficient resident memory CD8 T cells are functional in response to local peptide challenge, but only when in the presence of wild-type antigen-specific T cells. In the absence of an infection, memory-like or memory phenotype (MP) CD8 T cells can arise from homeostatic cytokine exposure during lymphopenia. In contrast to the role of ADAP after pathogen challenge, I have identified a negative regulatory role for ADAP in the formation of MP CD8 T cells in the steady state. Naïve ADAP-deficient CD8 T cells are hyperresponsive to lymphopenia in vivo and exhibit enhanced activation of STAT5 and homeostatic antigen-independent proliferation in vitro in response to IL-15. My results indicate that ADAP dampens naïve CD8 T cell responses to lymphopenia and IL-15, and demonstrates a novel antigen-independent function for ADAP in the suppression of MP CD8 T cell generation. These findings contribute to our knowledge of the generation of different memory CD8 T cell populations, and we hope to augment vaccine efficacy and better understand the formation and maintenance of memory CD8 T cells.