Publication Date




Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Microbiology and Immunology (Medicine)

Date of Defense


First Committee Member

Thomas R. Malek

Second Committee Member

Eckhard R. Podack

Third Committee Member

Wasif N. Khan

Fourth Committee Member

Maria T. Abreu

Fifth Committee Member

Krishna V. Komanduri

Sixth Committee Member

Todd M. Brusko


A network of mechanisms operates to maintain tolerance in the gut mucosa. CD103 marks many lymphoid cells, including regulatory T cells (Tregs), within the gut. CD103+ Tregs represent a subset of Tregs with potent suppressor function in vitro and in vivo. However, other features of this subset remain undefined. In current study, we found that CD103+ Treg subset exhibited a more activated phenotype and showed increased suppressive activity in preventing inflammation in the small intestine. We also showed that low IL-2R signaling had localized effect on CD103+ Treg subset in the peripheral lymphoid organ vs. tissue site. With respect to the function of CD103 in intestinal tolerance, CD103 may be part of a redundant pathway as CD103-/- mice do not exhibit autoimmunity. To reduce such redundancy, CD103-/- mice were crossed to mice (designated Y3) whose T cells expressed mutant IL-2Rß chains that lower IL-2R signaling. Unlike Y3 mice that only exhibit symptoms of a mild autoimmune attack, all Y3/CD103-/- mice rapidly developed severe colitis. The large intestine of these mice contained an increase in CD4+ T helper (Th)1 and Th17 effector cells and a reduced ratio of Tregs. Importantly, colitis was effectively prevented by the transfer of wild type (WT) Tregs into Y3/CD103-/- mice. Impaired intestinal tolerance was not attributed to an obvious lack of CD103-dependent gene regulation or intestinal homing/retention by Tregs nor a lack of functional activities typically associated with CD103+ dendritic cells (DCs), such as peripheral induced Treg (pTreg) development or imprinting CCR9 and a4ß7 homing molecules on Treg and T effector cells. Transcriptome analysis of Tregs was consistent with altered homeostasis due to impaired IL-2Rß-dependent signaling with minimal dysregulation added by the absence of CD103. Rather the absence of CD103 functioned to further dysregulate Treg homeostasis through a mechanism primarily associated with improper localization of the cells within the gut microenvironment that may prevent receiving optimal survival signals. Thus, IL-2Rß-dependent signaling and CD103 normally cooperate through distinctive processes to promote Treg homeostasis and immune tolerance.


Treg; IL-2R; CD103; Tolerance; IBD