A class of molecules that is expressed on antigen presenting cells, exemplified by CD80 (137), has been found to provide a necessary costimulatory signal for T cell activation and proliferation. CD28 and CTLA4 are the 137 counterreceptors and are expressed on the majority of human CD4+ T cells and many CD8+ T cells. The signal these molecules mediate is distinguished from other costimulatory signals by the finding that T cell recognition of antigen results in a prolonged state of T cell unresponsiveness or anergy, unless these costimulatory molecules are engaged. However, nearly half of the CD8+ and CD4−CD8− T cells lack CD28, and the costimulatory signals required for the activation ofsuch cells are unknown. To understand the pathways of activation used by CD28− T cells, we have examined the costimulatory requirements of antigen-specific CD4−CD8− TCR+-α/ß circulating T cells that lack the expression of CD28. We have characterized two T cell lines, DN1 and DN6, that recognize a mycobacterial antigen, and are restricted not by major histocompatibility complex class I or 11, but by CD1b or CD1c, two members of a family of major histocompatibility complexrelated molecules that have been recently implicated in a distinct pathway for antigen presentation. Comparison of antigen-specific cytolytic responses of the DN1 and DN6 T cell lines against antigen-pulsed CD1+ monocytes or CD1+ B lymphoblastoid cell lines (B-LCL) demonstrated that these T cells recognized antigen presented by both types of cells. However, T cell proliferation occurred only when antigen was presented by CD1+ monocytes, indicating that the CD1+ monocytes expressed a costimulatory molecule that the B-LCL transfectants lacked. This hypothesis was confirmed by demonstrating that the T cells became anergic when incubated with the CD1+-transfected B-LCL in the presence ofantigen, but not in the absence of antigen. The required costimulatory signal occurred by a CD28-independent mechanism since both the CD1+ monocytes and CD1+ B-LCL transfectants expressed 137-1 and 137-2, and DN1 and DN6 lacked surface expression of CD28. We propose that these data define a previously unrecognized pathway of costimulation for T cells distinct from that involving CD28 and its counterreceptors. We suggest that this 137-independent pathway plays a crucial role in the activation and maintenance of tolerance of at least a subset of CD28- T cells.
ASJC Scopus subject areas
- Immunology and Allergy