Abstract

An adaptive immune response is initiated by the proliferation and effector differentiation of numerically scarce and functionally inert naive lymphocytes following antigen encounter. CD8+ T cells, which eradicate cells infected with intracellular pathogens, rely on signals transduced through their antigen receptors (TCRs) and pro-inflammatory cytokine receptors to initiate both rapid clonal expansion and the acquisition of cytotoxic properties. The integration of these signals relies on activation-induced transcription factors that promote the expression of genes involved in cytotoxicity. However, activation limits the persistence and future proliferative capacity of cells that have responded to a primary antigen exposure, due to the simultaneous repression of quiescence-associated genes that are expressed in the naive state. The mechanisms coupling the upregulation of effector genes to the downregulation of quiescence-associated genes remain incompletely defined. Here, we identify the activation-induced transcriptional repressor Blimp1 as a direct repressor of TCF-1, a quiescence-associated transcription factor encoded by the Tcf7 gene. We disrupted TCF-1 downregulation in activated T cells through the ablation of cis-acting regulatory elements that recruited Blimp1 to the Tcf7 locus. Decoupling Tcf7 silencing from Blimp1-driven effector differentiation partially restored the proliferative potential of antigen-experienced CD8+ T cells. Analysis of the upstream signaling mediators involved in T cell activation revealed an unexpected requirement for Calcineurin, a TCR-activated phosphatase, in the preservation of TCF-1 expression and restraint of Blimp1 induction in activated CD8+ T cells. Conversely, the TCR-activated kinase p38 promoted TCF-1 downregulation in activated T cells. Thus, TCR signaling simultaneously engages pathways promoting and opposing effector and quiescent cell states. These observations invite the possibility that differential integration of the Calcineurin and p38 signaling modules downstream of TCR activation determines the persistence of T cells during responses to antigen.

Committee Chair

Takeshi Egawa

Committee Members

Chyi Hsieh; Gaya Amarasinghe; Kenneth Murphy; Nathan Singh

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Immunology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

6-25-2026

Language

English (en)

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Available for download on Friday, June 23, 2028

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