Date of Award

2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

In rabbits, the primary antibody repertoire is generated in the gut-associated lymphoid tissues (GALT), where bone marrow (BM)-derived B cells undergo a proliferative expansion and somatically diversify the immunoglobulin genes. Unlike in other species, B lymphopoiesis in rabbit arrests a few months after birth, and it is unclear how the peripheral B cell compartment is maintained when there is no influx of newly-made B cells from the BM.

For my dissertation, I investigated how B cells develop in the GALT of rabbits, and how they are maintained in adults after the arrest of lymphopoiesis. To identify cellular signals that promote B cell expansion in GALT, I introduced soluble decoy receptors into newborn rabbits and found that B cells in GALT expand in a B7-CD28 independent, CD40-CD40L, CR2-CR2L, and BAFF-BAFF-R dependent manner. Using several cross-reactive antibodies, I identified subpopulations of transitional (T1 and T2) B cells in the peripheral tissues of both young and adult rabbits. Unlike in other species, T1 B cells in rabbit were proliferating and were somatically diversified, suggesting that these B cells are not newly-made, but somehow maintained in the periphery of adults. Further, unlike in other species, I found that recombinant BAFF did not bind to primary B cells, and I demonstrated that this lack of binding was due to occupied BAFF-binding receptors. Taken together, my work provides some insights into how B cells develop and are maintained in adult rabbits. My work suggests that B cells in GALT develop in a T cell- independent and BAFF and complement-dependent manner. In adults, I designate the somatically diversified transitional B cells as T1d B cells and propose that they are maintained by self-renewal. I propose a model for peripheral B cell homeostasis in adults, wherein self-renewing T1d B cells continuously differentiate into mature B cells. Additionally, I propose that the chronic occupancy of BBRs on primary B cells with endogenous BAFF, provides B cells with a tonic/survival signal, and consequently allows them to remain long-lived.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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