MAJOR HISTOCOMPATIBILITY COMPLEX GENES DETERMINE NATURAL-KILLER-CELL TOLERANCE

Murine natural killer (NK) cell subsets, as defined by expression of m embers of the Ly49 gene family, discriminate target cells expressing d ifferent major histocompatibility complex (MHC) class I alleles. For e xample, Ly49A(+) NK cells lyse H-2(b) but not H-2(d) tumor target cell s. The specificity arises because D-d on target cells binds to Ly49A, transducing an inhibitory signal into the Ly49A(+) NK cells. The capac ity of NK cells to discriminate allelic class I determinants raises a key issue: are NK cells self-tolerant, and if so what are the mechanis ms that lead to self-tolerance? As previously reported, potentially au toaggressive Ly49A(+) NK cells are not clonally deleted in H-2(b) mice . However, IL-2-cultured Ly49A(+) effector cells from H-2(b) mice exhi bit reduced lysis of H-2(b) (self) concanavalin A blast target cells, compared to Ly49A(+) effector cells from H-2(d) mice. Possible mechani sms accounting for this self-tolerance are addressed in this report. S elf-tolerance was not due to anergy of the cells, because the Ly49A(+) effector cells from both types of mice lysed beta 2-microglobulin-def icient target cells efficiently and equivalently. These results also s uggest that tolerance results from inhibition mediated by beta 2m-depe ndent H-2(b) class I molecules. Significantly, blockade of Ly49A on Ly 49A(+) effector cells from H-2(b) mice did not restore lysis of H-2(b) target cells, suggesting that inhibition is not mediated through the Ly49A receptor. Additional experiments suggest that inhibition is also not mediated primarily through the Ly49C receptor. These results sugg est that Ly49A(+) effector cells from H-2(b) mice, unlike those from H -2(d) mice, express inhibitory receptors specific for H-2(b) molecules that are distinct from Ly49A and Ly49C.