Memory T cells enhance and diversify secondary GC responses

Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Craft, Joseph

Abstract

Humoral responses are tightly regulated. Inability to maintain proper humoral response results in succumbing to infections, malignant transformation or autoimmune diseases. T cells interact with B cells in both lymphoid organ and peripheral tissues, enhancing the magnitude of germinal center (GC) reaction and antibody production as well as affecting the affinity and effector function of antibodies. Secondary humoral responses involve rapid and enhanced antibody production and GC formation compared with primary responses. Memory B cells contribute to the majority of secondary plasma cell populations, while secondary GCs consist mostly of naïve B cell progenies. Though the role of memory B cells is well-studied, the function of memory T cells in secondary humoral responses remains incompletely understood. Our study demonstrates that memory T cells enhance antibody production and GC formation. This enhancement is coupled with an increased recruitment of naïve B cells into secondary GCs, which diversifies GC clonality. Mechanistically, memory T cells rapidly differentiate into T follicular helper (Tfh) cells with the ability to contact more B cells upon boosting. Negative feedback exists in restricting expansion of Tfh cells during secondary responses, as the number of Tfh cells contracts at the peak of GC responses through a cell-extrinsic way. CXCR5+ memory T cells are dominant in differentiating into Tfh cells upon boosting. The similarity and difference between memory Tfh cells and effector Tfh cells have been illustrated, while the signal molecules that specifically promote memory Tfh differentiation during primary responses have not been identified. In addition, whether GC-Tfh cells could become memory Tfh cells remain unknown. By tracing GC-Tfh progenies at memory timepoint, we revealed that GC-Tfh cells can survive until memory timepoint as efficiently as other memory Tfh precursors, where they downregulate CXCR5 and migrate to T-B border.

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