Requirements for Antigen-Specific T-Cell Activation: Two Roles for Class II MHC Gene Products.

Abstract

It is well established that Major Histocompatibility Complex (MHC) gene products are intimately involved in cellular immune responses. Although the MHC antigens play a key role as markers for self and nonself discrimination in immune responses, precise mechanisms for their action are not well known. In this research I studied the role for class II MHC (Ia) antigen in T-cell activation. To examine this I utilized a murine T cell hybridoma directed against a protein antigen PPD in association with I-A$\\sp{\\rm d}$(PPD/I-A$\\sp{\\rm d}$). I found that different APC utilize different pathways, intracellular or membrane-bound, to form the same PPD/I-A$\\sp{\\rm d}$ determinant recognized by the T cells. Thus, glutaraldehyde-fixed A20.JAD cells, a B lymphoma, were able to present PPD to the T cells. However, presentation by P388D1 cells, a macrophage-like line, was blocked by glutaraldehyde prior to exposure to PPD. It was also found that isolated plasma membranes prepared from PPD-pulsed APC stimulated the T cell efficiently, and solubilization of the stimulatory membranes destroyed the antigenic determinant. Since these results suggested that the antigen was retained on the APC membrane in a manner necessary for T cell recognition, I attempted to separate the functional roles of the PPD and Ia molecules by treating PPD-pulsed APC with anti-Ia antibodies. This treatment was thought to eliminate the stimulatory role of Ia on that cell while possibly maintaining the membrane-associated PPD that would alone be recognized by the T cells. I found that APC treated with anti-Ia antibodies could present PPD to the T cells in conjunction with a non-antigen-specific Ia function provided by another cell. These results indicate that Ia molecules are involved in antigen-specific T-cell activation in at least two different ways: one is to contribute to the presentation of PPD, and the second is a non-antigen-specific Ia-T cell interaction. These two Ia functions were required simultaneously to initiate T-cell activation, and the T cell structures responsible for the non-antigen-specific Ia interaction seemed to be clonally expressed. This suggests that these two Ia interactions with T cells are possibly mediated by the same clonally distributed TCR. These results have important implications for the mechanisms of T-cell recognition of APC-associated antigens in that TCR interact with Ia antigen alone as well as in association with nominal antigen, and both of these interactions with Ia are required for T-cell activation.