Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Michael P. Cancro

Abstract

An increasing body of work shows that T-bet+ B cells play important roles in immune responses to infections a well as in autoimmune diseases. These studies investigate the kinetics, tissue distribution, and functions of T-bet+ B cells in a murine influenza infection model. Both T-bet+ and T-bet- HA-specific B cells emerge early after infection, acquire the memory markers CD73, PD-L2 and CD80, and persist indefinitely with limited interconversion between T-bet+ and T-bet- B cell pools. Moreover, T-bet+ B cells are required for HA stalk specific antibodies and sustained protective HAI titers. T-bet+ HA-specific B cells can be further divided into T-bethigh and T-betlow B cell pools. While T-bethigh, T-betlow, and T-bet- HA-specific B cells are initially found in the spleen, lungs, and draining mediastinal lymph nodes; at later timepoints T-bethigh HA-specific memory B cells are restricted to the spleen, despite the continued presence of T-bet- HA-specific B cells at other anatomical locations. Parabiotic studies show that HA-specific T-bethigh B cells are splenic residents, whereas T-betlow and T-bet- B cells recirculate. T-bethigh B cells give rise to T-betlow B cells but T-betlow B cells do not become T-bethigh. However, T-betlow B cells persist for a minimum of three weeks in the absence of T-bethigh B cells, indicating that they are likely distinct populations. CD138 levels increase with decreasing T-bet expression and T-betlow and T-bethigh B cells downregulate T-bet and give rise to plasma cells. Both B220+ and B220- plasma cells arise from T-bet+ B cells in the spleen and bone marrow. Together, these data suggest that T-bethigh memory B cells are a unique splenic resident population with stem cell like properties that sustains plasma cell numbers and protective antibody titers long term.

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