CD40 Sustains T Cell Activation During Cognate Communication with Resting B Cells: a Dissertation

Abstract

T and B-lymphocytes play an important role in an adaptive immune response. Communication between these two cells may result in either a humoral immune response or tolerance. Communication between T and B-lymphocytes involves a number of inducible cell surface molecules on both T and B-lymphocytes. It was the aim of this project to gain a greater understanding of the role of CD40 in the dynamic communication that occurs between naïve T-lymphocytes and resting B-lymphocytes during cognate communication. Because in vivo antigen specific T-lymphocytes are at low frequency, it is difficult to examine antigen-specific naïve T-lymphocytes. Thus, an in vitro system employing naïve antigen-specific T cell receptor (TCR) transgenic T cells and small resting B-lymphocytes that did not express CD40 was devised to examine the role of CD40 in cognate communication between naïve T-lymphocytes and resting B-lymphocytes. Upon recognition of antigen on resting B-lymphocytes that expressed CD40, T-lymphocytes proliferated, expressed the activation antigens CD69 and CD25, and remained responsive to subsequent antigen challenge. In the absence of CD40, resting B-lymphocytes did not induce sustained proliferation or sustained expression of the activation markers CD69 and CD25 on naïve T-lymphocytes, and their recovery was decreased compared to naïve T-lymphocytes that recognized antigen on resting B-lymphocytes that expressed CD40. Naïve T-lymphocytes, however, remained responsive to subsequent antigen challenge after recognition of antigen on resting CD40-/- B-lymphocytes. Recognition of antigen on resting CD40-/- B-lymphocytes also resulted in increased recovery and antigen responsiveness of T-lymphocytes when compared to controls without antigen, The role of CD40 in sustaining activation of naïve T-lymphocytes may be unique to resting B-lymphocytes, since proliferation of naïve T-lymphocytes in response to dendritic cells that did not express CD40 was similar to proliferation of naïve T-lymphocytes in response to dendritic cells that expressed CD40. The mechanism by which CD40 sustained activation of naïve T-lymphocytes was investigated by examining the induction of various costimulatory molecules on resting CD40+/- and CD40-/- B-lymphocytes during cognate interaction with naive T-lymphocytes. Induction of B7-1, upregulation of CD44 and ICAM-1, and sustained but not initial induction of B7-2 required that CD40 be expressed on resting B-lymphocytes. Expression of B7-1 and CD44H was not required for proliferation of naïve T-lymphocytes in response to antigen presented on resting B-lymphocytes. However, sustained expression of B7-2 was crucial for proliferation of naïve T-lymphocytes in response to antigen presented on resting B-lymphocytes.