Evidence for involvement of dual-function T cells in rejection of MHC class I disparate skin grafts. Assessment of MHC class I alloantigens as in vivo helper determinants

Abstract

The present study further characterizes the cellular mechanisms involved in the in vivo rejection of MHC class I-disparate skin allografts. Previously, we demonstrated that class I-specific rejection responses could result from collaborations between distinct populations of lymphokine-secreting T helper (Th) and lymphokine-responsive T effector (Teff) cells. In the present study, we have assessed the possibility that class I-specific rejection responses could also result from a second cellular mechanism involving a single population of dual-function Th/Teff cells that would not have any further requirement for cell-cell collaboration. Our experimental strategy was to determine the ability of MHC class I-allospecific T cells, in response to class I allodeterminants expressed on skin grafts, to provide help in vivo for activation of helper-dependent Teff cells. We found that class I anti-Kbm1-allospecific T cells would reject bm1 skin allografts, but would not generate help for the activation of helper-dependent effector cells that were specific for third-party skin allografts (e.g., grafts expressing Kbm6, Qa1a, or H-Y allodeterminants). This failure of anti-Kbm1 T cells to provide help in response to bm1 skin allografts was not due to an inability of lymphokine-secreting anti-Kbm1 Th cells to recognize and respond in vivo to Kbm1 allodeterminants expressed on skin, since lymphokine-secreting anti-Kbm1 Th cells were specifically primed in animals engrafted with bm1 skin allografts. Nor was any evidence found that this failure was due to active suppression of anti-Kbm1 helper activity. Rather, we found that anti-Kbm1 T cells consumed nearly all of the helper factors they secreted. Taken together, these results are most consistent with the in vivo activity of dual-function Th/Teff cells that consume the lymphokines they secrete. Thus, this study demonstrates that MHC class I-disparate skin allografts can be rejected by two mechanisms, depending on the ability of the allospecific Teff cell to secrete helper lymphokines. MHC class I-disparate grafts can be rejected by (a) class I-allospecific Teff cells that are unable to produce lymphokine but are responsive to exogenous T cell help; and (b) class I-allospecific dual-function Th/Teff cells that are able to both produce and consume soluble lymphokine.