UBC Theses and Dissertations
Regulation of intestinal inflammation by CD45 Samarakoon, Asanga
Factors secreted by intestinal immune cells such as retinoic acid and cytokines are crucial in maintaining homeostasis in the gut. Dysregulation in the secretion of these factors can lead to inflammation and development of colitis. CD45 is a leukocyte specific tyrosine phosphatase important for T cell development and antigen receptor signaling. Here, I show that upon DSS-induced colitis, CD45-/- mice unexpectedly have significant numbers of T cells in their colon and exhibit more severe colitis. This was attributed to increased expression of the gut homing molecule, α4β7 and increased production of IFNγ and IL17A by the CD45-/- T cells. However, in the absence of adaptive immunity, CD45 is required for optimal intestinal innate immune responses. CD45-/- innate lymphoid cells had decreased IL-22 and GM-CSF production and CD45-/- myeloid cells have lower retinoic acid production. This led to less severe colitis when CD45 ⁺/⁺ T cells were transferred into CD45RAG-/- mice as it led to reduced expression of gut homing molecules and reduced homing of T cells to the colon. This defect was corrected by the addition of GM-CSF, which restored retinoic acid production. Induction of colitis by the transfer of naïve T cells into RAG-/- and CD45RAG-/- mice delayed the development of systemic disease in CD45RAG-/- mice, but led to comparable intestinal inflammation at the RAG-/- weight loss endpoint and significantly greater inflammation at the CD45RAG-/- endpoint, corresponding with increased CD45-/- myeloid cells in the colon. Since there was no difference in Foxp3+ regulatory T cells systemically, other options of inhibition of systemic inflammation in CD45RAG-/- mice were explored. CD45RAG-/- mice had increased CD71+TER119+ erythroid cells in the spleen prior to and post colitis induction and failed to downregulate erythroid progenitors upon T cell induced colitis. These suppressive erythroid cells may contribute to the delayed systemic inflammation in these mice. Overall, these results show novel roles for CD45 in the regulation of innate and adaptive immune cell cytokine production, as well as in erythrocyte maturation.
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