RESUMEN
Th2-type inflammation spontaneously shown in Bcl6-knockout (KO) mice is mainly caused by bone marrow (BM)-derived nonlymphoid cells. However, the function of dendritic cells (DCs) in Bcl6-KO mice has not been reported. We show in this article that the numbers of CD4(+) conventional DCs (cDCs) and CD8α(+) cDCs, but not of plasmacytoid DCs, were markedly reduced in the spleen of Bcl6-KO mice. Generation of cDCs from DC progenitors in BM cells was perturbed in the spleen of irradiated wild-type (WT) mice transferred with Bcl6-KO BM cells, indicating an intrinsic effect of Bcl6 in cDC precursors. Although cDC precursors were developed in a Bcl6-KO BM culture with Fms-like tyrosine kinase 3 ligand, the cDC precursors were more apoptotic than WT ones. Also p53, one of the molecular targets of Bcl6, was overexpressed in the precursors. The addition of a p53 inhibitor to Bcl6-KO BM culture protected apoptosis, suggesting that Bcl6 is required by cDC precursors for survival by controlling p53 expression. Furthermore, large numbers of T1/ST2(+) Th2 cells were naturally developed in the spleen of Bcl6-KO mice. Th2 skewing was accelerated in the culture of WT CD4 T cells stimulated with Ags and LPS-activated Bcl6-KO BM-derived DCs, which produced more IL-6 and less IL-12 than did WT DCs; the addition of anti-IL-6 Abs to the culture partially abrogated the Th2 skewing. These results suggest that Bcl6 is required in cDC precursors for survival and in activated DCs for modulating the cytokine profile.
Asunto(s)
Antígenos CD4/biosíntesis , Antígenos CD8/biosíntesis , Diferenciación Celular/inmunología , Proteínas de Unión al ADN/fisiología , Células Dendríticas/inmunología , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Células de la Médula Ósea/efectos de la radiación , Antígenos CD4/efectos de la radiación , Antígenos CD8/efectos de la radiación , Diferenciación Celular/genética , Diferenciación Celular/efectos de la radiación , Células Cultivadas , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/efectos de la radiación , Células Dendríticas/efectos de la radiación , Células Dendríticas/trasplante , Linfopenia/genética , Linfopenia/inmunología , Linfopenia/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-bcl-6 , Bazo/inmunología , Bazo/patología , Bazo/efectos de la radiaciónRESUMEN
OBJECTIVES: Mixed hematopoietic chimerism is associated with islet allograft tolerance and may reverse autoimmunity. We developed low intensity regimens for the induction of mixed chimerism and examined the effects on autoimmunity in prediabetic nonobese diabetic (NOD) mice. RESEARCH DESIGN AND METHODS: NOD mice received various combinations of total body irradiation, anti-CD154, anti-CD8alpha, anti-CD4, and anti-Thy1.2 monoclonal antibodies, with or without transplantation of C57BL/6 bone marrow cells and were followed up for development of diabetes, chimerism, and donor skin graft survival. Autoimmunity was assessed by histologic examination of salivary glands and pancreata. RESULTS: Although conditioning alone prevented or delayed the onset of diabetes, stable mixed chimerism was required for the reversal of isletitis. Mixed chimerism and skin graft tolerance were achieved in NOD mice receiving anti-CD154 with bone marrow transplantation as the means of tolerizing peripheral CD4 T cells to alloantigens. However, isletitis was not reversed in allotolerant mixed chimeras prepared with this regimen. CONCLUSIONS: Partial depletion of peripheral autoreactive NOD CD4 T cells is needed to achieve full reversal of isletitis by mixed chimerism induction from a protective donor strain, but it is not required for induction of specific tolerance to donor alloantigens. Thus, the requirements for tolerizing alloreactive and autoreactive NOD CD4 cells are distinct.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Trasplante de Islotes Pancreáticos/inmunología , Ratones Endogámicos NOD/inmunología , Trasplante de Piel/inmunología , Quimera por Trasplante/inmunología , Trasplante Homólogo/inmunología , Traslado Adoptivo , Animales , Autoinmunidad , Linfocitos T CD4-Positivos/inmunología , Ligando de CD40/inmunología , Ligando de CD40/efectos de la radiación , Antígenos CD8/inmunología , Antígenos CD8/efectos de la radiación , Femenino , Citometría de Flujo , Islotes Pancreáticos/inmunología , Isoantígenos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos , Estado Prediabético/inmunología , Antígenos Thy-1/inmunología , Antígenos Thy-1/efectos de la radiación , Irradiación Corporal TotalRESUMEN
OBJECTIVE: To find effects of low dose radiation (LDR) induced proteins on lymphocyte subsets. METHOD: Stimulative effects of LDR-induced proteins on human peripheral blood lymphocyte subsets were studied. RESULT: The 14C-TdR incorporation in CD4, CD8, CD19 cells increased by 118.23%, 115.18% and 121.62% respectively compared with control group. CONCLUSION: LDR induced proteins can stimulate proliferation of CD4, CD8 and CD19 cells.
Asunto(s)
Activación de Linfocitos/efectos de la radiación , Subgrupos Linfocitarios/efectos de la radiación , Antígenos CD19/efectos de la radiación , Antígenos CD4/efectos de la radiación , Antígenos CD8/efectos de la radiación , Supervivencia Celular/efectos de la radiación , Humanos , Dosis de RadiaciónRESUMEN
The objective of these studies was to determine the effect of low X-ray doses on peripheral blood lymphocytes in the workers operating X-ray equipment. In 30 workers and 18 persons who constituted the control group the absolute number of peripheral blood lymphocytes, the number of T CD4+ and T CD8+ lymphocytes, the ratio CD4+/CD8+ and the concentration of serum interleukins (IL-2, IL-4, IL-6) were tested. Subgroups with respect to sex and employment period were selected. A significant increase in IL-2 concentration in workers as compared to controls was observed and significantly decreased IL-4 level in operating X-ray equipment was revealed. The lowest levels of IL-4 were noted in the women subgroup. A high positive, statistically significant correlations between the number of lymphocytes and the concentration of IL-2 and the level of IL-4 were observed. Moreover, our studies revealed that lymphocyte number and interleukin concentrations in serum of X-ray operators do not depend on the assumed ranges of the length of employment period.
Asunto(s)
Interleucinas/sangre , Linfocitos/efectos de la radiación , Exposición Profesional , Radiología , Adulto , Anciano , Antígenos CD4/efectos de la radiación , Antígenos CD8/efectos de la radiación , Estudios de Casos y Controles , Femenino , Humanos , Linfocitos/sangre , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
Acute, low-doses of ultraviolet (UV)-B radiation affect the immune competent cells of the skin immune system. In this study, we examined the time-dependent changes of the cutaneous T cell population in normal human volunteers following a single local exposure to UV. Solar-simulated UV radiation caused an initial decrease in intraepidermal T cell numbers, even leading to T cell depletion at day 4, whereupon a considerable infiltration of T cells in the epidermis occurred that peaked at day 14. In the dermis the number of T cells was markedly increased at days 2 (peak) and 4 after irradiation, and subsequently declined to the nonirradiated control values at day 10. Double-staining with several T cell markers showed that the T cells, infiltrating the (epi)dermis upon UV exposure, were almost exclusively CD4+ CD45RO+ T cells, expressing an alpha/beta type T cell receptor, but lacking the activation markers HLA-DR, VLA-1, and IL-2R. Application of UVB radiation resulted in similar dynamics of T cells, indicating that the UVB wavelengths within the solar-simulated UV radiation were responsible for the selective influx of CD4+ T cells. In conjunction with UVB-induced alterations in the type and function of antigen-presenting cells (i.e., Langerhans cells and macrophages), the changes of the cutaneous T cell population may also contribute to UVB-induced immunosuppression at skin level in man.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/efectos de la radiación , Piel/inmunología , Piel/efectos de la radiación , Rayos Ultravioleta , Adolescente , Adulto , Complejo CD3/análisis , Antígenos CD4/biosíntesis , Antígenos CD4/inmunología , Antígenos CD4/efectos de la radiación , Linfocitos T CD4-Positivos/citología , Antígenos CD8/biosíntesis , Antígenos CD8/inmunología , Antígenos CD8/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Memoria Inmunológica/efectos de la radiación , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/efectos de la radiación , Piel/citología , Luz Solar/efectos adversos , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/efectos de la radiación , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Factores de TiempoRESUMEN
The development of CD8+ intestinal intraepithelial T lymphocytes (IEL) was analyzed in mice that are deficient in the expression of MHC class I molecules, owing to either a mutated beta 2-microglobulin (beta 2m) gene or a mutated transporter associated with Ag processing 1 (TAP1) gene, and in mice doubly homozygous for beta 2m and TAPI mutations. In all mutant mice, the population size of major CD8 alpha alpha+ and CD8 alpha beta+ alpha beta-IEL subsets was reduced drastically, and this resulted in a conspicuous decrease in the total number of alpha beta-IEL. Concomitantly, a compensatory two- to threefold increase in the number of gamma delta-IEL consisting mostly of CD8 alpha alpha+ subset was noted. In radiation bone marrow chimeras, this wild-type/mutant phenotype was determined by the genotype of radioresistant host cells, but was not determined by the genotype of reconstituting bone marrow-derived cells. In beta 2m X TCR-delta double mutant mice, however, the CD8 alpha alpha+ but not CD8 alpha beta+ alpha beta-IEL subset expanded dramatically. Thus, in the absence of gamma delta-IEL, alpha beta-IEL in beta 2m-deficient mice outnumbered those in wild-type littermates. These results indicate that the generation of CD8 alpha alpha+ lymphocyte population of alpha beta- and gamma delta-IEL is not dependent, but that of CD8 alpha beta+ lymphocyte population of alpha beta-IEL is dependent on beta 2m- and/or TAP1-dependent MHC class I molecules, expressed by the controlling cells present in the anatomical site, where the development of IEL takes place.