RESUMEN
In this study we compare the effects of cyclosporin A (CsA), FK520 (an agent similar to FK506), and rapamycin (RAPA) on peripheral T-cell deletion induced by either superantigens or anti-TCR alpha beta mAb, and on anergy induced by superantigens in mice. CsA enhanced T-cell deletion and blocked anergy induction (in residual T cells), while FK520 and RAPA had no effects on these processes. CsA also enhanced apoptosis of stimulated T cells in vitro, where cell death occurred without prior proliferation and in the absence of phagocytes. Our data suggest that CsA exerts these effects through a calcineurin-independent pathway, and this may be relevant to the development of tolerance in some models.
Asunto(s)
Inmunosupresores/farmacología , Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Linfocitos T CD4-Positivos/inmunología , Anergia Clonal/efectos de los fármacos , Supresión Clonal/efectos de los fármacos , Ciclosporina/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Polienos/farmacología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Sirolimus , Superantígenos/inmunología , Linfocitos T/efectos de los fármacos , Tacrolimus/análogos & derivados , Tacrolimus/farmacologíaRESUMEN
Peripheral CD4-CD8- (double negative) T cells (DNT cells) that express TCR-alpha/beta (DNT-alpha/beta cells) are expanded in some autoimmunity-prone mice, but in normal mice these cells have not been extensively studied. In this study, we isolated splenic DNT-alpha/beta cells that are Thy-1+, Ly-1+, MAC-1-, J11d-, and Ia-. Only 5% of these cells were B220+. Freshly isolated DNT-alpha/beta cells did not proliferate in MLC; however, these cells responded strongly to stimulation with matrix-bound anti-TCR-alpha/beta antibodies or Con A. After activation the cells became CD4+CD8-, acquired high reactivity in both syngeneic and allogeneic MLC, but lacked cytotoxicity. After activation the cells gradually reverted to a double-negative phenotype in culture. Surprisingly, despite high autoreactivity the analysis of TCR V beta expression revealed a near normal pattern of Mls-1a- and I-E-induced clonal deletions. These findings reveal that DNT-alpha/beta cells are subject to negative selection and that autoreactivity cannot be attributed to a general failure of clonal deletion in this T cell subpopulation. DNT-alpha/beta cells may normally remain tolerant by down-regulating the CD4 molecule.
Asunto(s)
Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos CD4/análisis , Antígenos CD8/análisis , Células Clonales , Citotoxicidad Inmunológica , Femenino , Citometría de Flujo , Genes , Activación de Linfocitos , Prueba de Cultivo Mixto de Linfocitos , Ratones , Bazo/citologíaRESUMEN
Diabetes in NOD mice is an autoimmune disease which is characterized by the infiltration of islets of Langerhans by large numbers of T cells. Some of these infiltrating T cells are clearly islet-cells-specific; however, many or most of these T cells could be attracted nonspecificity into these lesions. To study NOD pancreas-infiltrating T cells, we fused these cells with BW5147 to make T cell hybridomas. Ninety-four pancreas-derived T hybrids were analyzed of which 12 responded specifically to islet cells by secreting IL-2. Only CD3+, CD4+ hybrids responded to islet cells in our assay, and a large proportion of these hybrids were islet-cell reactive. T cell receptor (TCR) V beta element usage was heterogeneous in islet-reactive hybridomas.
Asunto(s)
Hibridomas/inmunología , Páncreas/inmunología , Linfocitos T/inmunología , Animales , Animales Recién Nacidos , Antígenos de Diferenciación de Linfocitos T/inmunología , Complejo CD3 , Antígenos CD4/inmunología , Antígenos CD8/inmunología , Diabetes Mellitus Tipo 1/inmunología , Hibridomas/metabolismo , Interleucina-2/metabolismo , Islotes Pancreáticos/inmunología , Ratones , Ratones Endogámicos NOD , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
We examined the generation of suppressor cells in the popliteal lymph nodes (PLN) of F1 recipients of parental spleen cells in rats, i.e., a local form of graft-vs-host disease (GVHD). PLN cells of F1 recipients, or subpopulations of these cells, were tested for their ability to suppress the mixed lymphocyte culture and cell-mediated lympholysis. Suppressor cells were consistently generated in this local GVHD reaction. In contrast to others, we found no evidence that suppression was mediated by T cells. Instead, the suppressor cells had the CD5-, CD8+, asialo-GM1+ phenotype characteristic of rat NK cells. The suppression exerted by these cells was nonspecific and was not mediated by a veto effect. The suppressor cells did not kill alloreactive T cell blasts, but had strong NK activity. These cells appear to be of donor origin. These local-GVHD-associated NK-like suppressor cells are similar, but not identical, to the natural suppressor cells described by other investigators in various experimental systems.