Murine syngeneic mixed lymphocyte response. I. Target antigens are self Ia molecules

Abstract

A system has been described that produces a murine syngeneic mixed lymphocyte response (MLR) comparable in magnitude to an allogeneic MLR. The responder cells in these cultures exhibit the classic immunologic characteristics of both memory and specificity. Studies using radiation-induced bone marrow chimeras of F(1) {arrow} parent type indicated that, similar to many other T cell-mediated immune responses, the response of the T lymphocytes in the syngeneic MLR was major histocompatibility complex-restricted and was determined by the environment in which the T cells matured. Using responder T cells from F(1) {arrow} parent chimeras and stimulator cells from H-2 recombinant strains, it was possible to map the genes involved in the stimulation to the K and/or I regions. In addition, blocking studies with monoclonal anti-Ia antibodies suggested that in the B10.A strain the critical molecules were products of both the I-A(k) and I-E(k) subregions. The issue of whether the syngeneic MLR is directed solely at self I-region antigens or whether the response represents proliferation to an unknown antigen in association with self I-region determinants was also addressed. Secondary syngeneic MLR were successfully performed in normal mouse serum and with stimulator cells prepared in the absence of bovine serum albumin to rule out the possibility that xenogeneic serum antigens were involved in the stimulation. The possibility that the syngeneic MLR might represent a secondary response to environmental antigens was eliminated by using germ- free mice as a source of stimulator cells and by demonstrating that spleen cells from unimmunized, fully allogeneic chimeras (B10.A {arrow} B10) could generate a normal syngeneic MLR even though such chimeras could not be primed to respond to any foreign antigens unless supplemented in vivo with a source of antigen-presenting cells syngeneic to the B10 host. The possibility that the syngeneic MLR was a primary response to a foreign antigen was considered unlikely because by using our culture conditions we could not obtain a primary antigen response or a secondary antigen response after in vitro priming to a variety of potent foreign antigens. Finally, the possibility that the syngeneic MLR represents a response to a variety of minor histocompatibility self antigens in association with self Ia molecules was eliminated by showing that the secondary responses to H-2 compatible, non-H-2 different strain (A/J vs. B10.A and C3H, or BALB/c vs. B10.D2 and DBA/2) were comparable to the secondary responses to syngeneic stimulators. Thus, we conclude that the target antigens in the syngeneic MLR are solely determinants on self Ia molecules, although the functionally equivalent possibility of a single, nonpolymorphic, minor self antigen seen in association with self Ia molecules cannot be excluded.

Spontaneous internalization of Class I major histocompatibility complex molecules in T lymphoid cells.

“…Note that Table I also shows an increase of intraceilular H-2K-positive lymphocytes for untreated cells cultured over 3 d. This phenomenon might have been the consequence of syngeneic stimulation under in vitro culture conditions as reported for murine spleen lymphocytes (15,16).…”

Alterations in the Proliferative Responses of T Cells from Aged and Chimeric Mice

“…Since peripheral T cells are known to have been se lected for their low affinity for self-MHC but show high cross-reactivity to alloantigens [30][31][32], it was concluded that there exist disturbances in the T cell repertoire in aged mice. The loss of alloreactivity of aged T cells should naturally coincide with the de creased auto-MLR, as the former reflects the MHC restriction specificities of T cells having low affinity for self-MHC [33,34], In order to learn whether such age-dependent changes in the alio-and autoreactivity of T cells are inherent to the stem cells from which T cells differen tiate, we performed experiments with bone marrow chimeras. The essential findings were (1) that T cells from old bone marrow-young host chiemeras be haved like young T cells in both alio-and autoreactiv ity, and (2) that T cells from young -old chimeras re sponded to alio-and autostimulators in a pattern very similar to that of old T cells.…”

Neonatal injections of cyclosporin enhance autoimmune diabetes in non-obese diabetic mice

“…However, male NOD mice display a lower spontaneous incidence of overt diabetes than females, revealing a mechanism, presumably via suppressor T cells [25], which prevents the progression of disease once insulitis is present. This resistance of male NOD mice to overt diabetes is linked to androgens [41] and results from suppressive mechanisms that can be abrogated in adults by cyclophosphamide [42][43][44], In our study, the effects induced by neonatal injections of CsA were sufficient to overcome all the safety devices which are blocked up in male NOD, Neonatal injections of CsA depressed the SMLR, which is a T cell response to self MHC class II molecules generating suppressor cells [18][19][20][21][22][23][24][25] and which is already decreased in NOD mice compared with other strains [25], Taken together, these data suggest that the neonatal CsA injections have produced a deficiency of the suppressive mechanisms involved in the resistance of male NOD mice. The time of beginning CsA administration could have been critical for enhancement of the disease.…”

“…The possible mechanisms underlying the clinical effects were investigated by analysing the phenotype of thymocyte and splenocyte subsets. Lymphocyte functions were also evaluated by mitogenesis induced by concanavalin A (Con A), or by xenogeneic insulin-producing cell extracts, or during the syngeneic mixed lymphocyte reaction which is a T cell response to self MHC class II molecules generating suppressor cells [18][19][20][21][22][23][24][25].…”