The role of CD22 and Bim expression as determinants for the regulation of antigen-specific adaptive immune responses
Ma, Daphne Yin-Wai
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University of Washington Abstract The role of CD22 and Bim expression as determinants for the regulation of antigen-specific adaptive immune responses Daphne Yin-Wai Ma Chair of the Supervisory Committee: Professor Edward A. Clark Department of Immunology West Nile Virus (WNV) is a RNA virus of the family Flaviviridae and the leading cause of mosquito-borne encephalitis in the United States. Humoral immunity is essential for protection against WNV infection; however, the requirements for initiating effective antibody responses against WNV infection are still unclear. CD22 (Siglec-2) is expressed on B cells and regulates B cell receptor signaling, cell survival, proliferation and antibody production. Here we investigated how CD22 contributes to protection against WNV infection. We found that CD22 knockout (Cd22-/-) mice were highly susceptible to WNV infection and had increased viral loads in the serum and central nervous system (CNS) compared to wildtype (WT) mice. This outcome was not due to a defect in humoral immunity as Cd22-/- mice had normal WNV-specific antibody responses. However, Cd22-/- mice had decreased WNV-specific CD8+ T cell responses compared to WT mice. These defects were not simply due to reduced proliferation or increased cell death, but rather were associated with decreased lymphocyte migration into the draining lymph nodes (dLNs) of infected Cd22-/- mice. Cd22-/- mice had reduced production of the chemokine CCL3 in the dLNs after infection, suggesting that CD22 affects chemotaxis via controlling chemokine production. CD22 was not restricted to B cells but was also expressed on a subset of splenic DCIR2+ dendritic cells that rapidly expand early after WNV infection. Thus, CD22 plays an essential role in controlling WNV infection by governing immune cell migration and CD8+ T cell responses. In addition to CD22, the lifespan of a DC also affects the quality of adaptive immune responses. We found that DCs from mice lacking Bim, a pro-apoptotic protein of the Bcl-2 (B cell lymphoma -2) family, had prolonged lifespan in culture. The loss of Bim expression resulted in inability of DCs to promote BCR and antigen -induced B cell proliferation, regardless of maturation status. Long-lived DCs from Bim-/- mice also produced more IL-6 and had reduced expression of genes encoding BAFF and APRIL, all cytokines that affect B cell proliferation and survival. Thus both CD22 and Bim are important regulators of adaptive immune responses, and can specifically affect DC-mediated regulation of antigen-specific T and B cell response.
- Immunology