Date of Award

2025-04-01

Degree Name

Doctor of Philosophy

Department

Biosciences

Advisor(s)

Charlotte M. Vines

Abstract

C-C chemokine receptor 7 (CCR7) is critical in guiding T cell migration within the thymus and peripheral lymphoid tissues, shaping the adaptive immune response by promoting central tolerance and regulating immune homeostasis. Although its role in lymphocyte trafficking is well established, the molecular mechanisms by which CCR7 influences thymocyte development and T cell receptor (TCR) repertoire formation remain less understood. This study examines how CCR7 deficiency impacts thymic selection, TCR diversity, and the signaling events that shape repertoire restriction. Using a homozygously deleted CCR7 murine model, we found that the absence of CCR7 results in a less restricted TCR repertoire than wild-type mice, failing to eliminate potentially auto-reactive T cell clones properly. Our data revealed that CCR7 signaling during double negative (DN) stages of thymocyte development restricts TCRβ diversity by limiting J-segment trimming. Stimulation of CCR7 by its ligands at this stage enhances TCR signaling through the ZAP-70/LAT/PLCγ1 pathway, reinforcing the kinetic proofreading mechanisms essential for the discrimination of self and non-self antigens. Importantly, the broader and less selective TCR repertoires in the CCR7-deficient animals correlate with elevated antibody titers and immune dysregulation. These findings define a previously unrecognized function of CCR7 in thymocyte development, TCR function and supporting immune tolerance. Our findings aim to elucidate the molecular mechanisms through which CCR7 contributes to immune regulation, offering important insights for the development of novel immunotherapeutic strategies and approaches to immune modulation.

Language

en

Provenance

Received from ProQuest

File Size

88 p.

File Format

application/pdf

Rights Holder

Jaisel Amilcar Cervantes

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