RESUMEN
T-Cell antigen Receptor (TR) repertoire is generated through rearrangements of V and J genes encoding alpha and beta chains. The quantification and frequency for every V-J combination during ontogeny and development of the immune system remain to be precisely established. We have addressed this issue by building a model able to account for Valpha-Jalpha gene rearrangements during thymus development of mice. So we developed a numerical model on the whole TRA/TRD locus, based on experimental data, to estimate how Valpha and Jalpha genes become accessible to rearrangements. The progressive opening of the locus to V-J gene recombinations is modeled through windows of accessibility of different sizes and with different speeds of progression. Furthermore, the possibility of successive secondary V-J rearrangements was included in the modelling. The model points out some unbalanced V-J associations resulting from a preferential access to gene rearrangements and from a non-uniform partition of the accessibility of the J genes, depending on their location in the locus. The model shows that 3 to 4 successive rearrangements are sufficient to explain the use of all the V and J genes of the locus. Finally, the model provides information on both the kinetics of rearrangements and frequencies of each V-J associations. The model accounts for the essential features of the observed rearrangements on the TRA/TRD locus and may provide a reference for the repertoire of the V-J combinatorial diversity.
Asunto(s)
Reordenamiento Génico de la Cadena alfa de los Receptores de Antígenos de los Linfocitos T/genética , Genes Codificadores de la Cadena alfa de los Receptores de Linfocito T , Genes Codificadores de la Cadena delta de los Receptores de Linfocito T , Modelos Inmunológicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Animales , Simulación por Computador , Reordenamiento Génico de la Cadena delta de los Receptores de Antígenos de los Linfocitos T/genética , Ratones , Ratones Endogámicos BALB C , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND/AIMS: The fate of intrahepatic NK cell subsets in the course of HCV and HBV infections is not clearly understood. METHODS: Blood and intrahepatic CD56(+) NK cell subsets (expressing NKG2A, CD158a,h or CD158b,j receptors) from HCV or HBV patients were quantified by flow cytometry and localized by immunohistochemistry in liver biopsies. RESULTS: A significant reduction in NK cell frequency and a quantitative imbalance between CD56(bright) and CD56(dim) subsets were observed in chronic HCV patients as compared to HBV patients, underlining that the inflammatory environment is not the only cause of these phenomena. The proportions of intrahepatic NK cells expressing either NKG2A, and/or CD158a,h, CD158b,j differed significantly between HCV and HBV patients. A higher frequency of perforin among intrahepatic CD56(+)CD3(-) cells was observed in HCV compared to HBV patients. Double immunohistochemical staining showed that CD56(+)CD3(-) cells were localized within necrotic areas. Immune monitoring of circulating CD56 subsets revealed that CD3(-)CD56(bright)NKG2A(+) and CD3(-)CD56(dim)NKG2A(+) cells were positively correlated with the necroinflammatory score and inversely correlated with viral load, respectively, in HCV patients. CONCLUSIONS: HCV and HBV affect NK cell subsets according to the status of the diseases, especially CD3(-)CD56(dim)NKG2A(+) and CD3(-)CD56(bright)NKG2A(+) cells, may be of interest for disease monitoring.
