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The impact of CD45 on dendritic cell activation and tolerogenic response

University of British Columbia

Dendritic cells (DCs) are potent antigen presenting cells that orchestrate the immune system to mediate either a pro- or anti-inflammatory response, by provision of critical instructive signals to T cells. The leukocyte-specific tyrosine phosphatase CD45 can influence the immune response by its ability to act as either a positive or negative regulator of DC pro-inflammatory cytokine production. This dissertation explores the effect of CD45 in mediating a tolerogenic response in DCs. The lack of CD45 in bone marrow derived dendritic cells (BMDCs) was found to cause a preferential production of IL-10 in response to LPS stimulation, despite the mature DC phenotype defined by elevated expression levels of MHCII and co-stimulatory molecules CD80 and CD86, and the unaffected ability of CD45 deficient BMDCs to drive naïve CD4⁺ T cells or CD4⁺ Foxp3⁺ regulatory T cell (Treg) proliferation in vitro. An important in vivo finding was that CD45 deficiency in RAG-/- mice provided greater protection against wasting disease in the Treg mediated prevention of experimental colitis. This survival advantage was found to correlate with an increased proportion of Tregs at the colonic lamina propria in CD45 deficient RAG-/- mice. Culture of BMDC precursors with the anti CD45RB antibody generated BMDCs with reduced LPS-induced IL-12 production and T cell stimulatory capacity implicating CD45RB expression in the promotion of tolerogenic responses in DCs. Rapamycin, a pharmacological inhibitor of the mTOR pathway, was found to have a minimal effect on inducing a tolerogenic DC from BMDCs generated by culture in GM-CSF alone. However rapamycin exhibited a more profound suppressive effect on the ability of CD45 deficient DCs to drive T cell proliferation in vitro. Overall this study suggests that the CD45RB isoform may specifically inhibit an inflammatory response in DCs but the loss of all CD45 isoforms in DCs may potentially mediate T tolerance through immune deviation, while the loss of CD45 in multiple innate immune cells may culminate in an environment that promotes Treg expansion or function in vivo.

Text

2012-08-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/43101

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/