ROLE OF THE TCR BINDING REGION OF THE HLA CLASS-I ALPHA-2 DOMAIN IN REGULATION OF CELL-ADHESION AND PROLIFERATION

In addition to Ag presentation for T cell surveillance, MHC molecules have been implicated in mediating regulatory signals. We have assessed biologic responses following engagement of the TCR accessible region of the HLA class I alpha 2 domain. mAbs directed to this domain specif ically induced cell aggregation of normal hematopoietic and leukemic c ells. The functional consequences were unique since other mAbs reactiv e with HLA class I residues outside the TCR binding domain did not ind uce cell aggregation. The;adhesion response required ATP, mRNA, protei n, and actin synthesis and did not depend on LFA-1/ICAM interactions. Cell aggregation was also induced when all but four of the intracytopl asmic residues of the class I molecule were deleted, indicating that t ransduction of signals leading to cell adhesion does not require this portion of the molecule. mAbs directed to HLA class I alpha 2 amino ac id residues within the TCR binding domain were also able to inhibit pr oliferation of normal mitogen-stimulated T cells. Growth inhibition co rrelated with down-regulated expression of CD25, CD28, and CD95, sugge sting that reduced transduction of costimulatory signals is involved. Although HLA class I signals inducing cell aggregation required engage ment of positions within the TCR binding region, growth inhibitory sig nals could be generated through positions both within and adjacent to this domain. Taken together, engagement of specific positions within t he TCR binding domain of the class I alpha 2 helix results in active c ellular responses. Thus, this region may be directly involved in signa l transduction following CTL recognition of target cells.