Proteasoma, subtipos y sus implicaciones en la tolerancia central / The proteasome: subtypes and involvement in central tolerance

El proteasoma es un complejo proteico grande, el cual se encuentra fundamentalmente en todas las células eucariotas ya que juega un rol muy importante en los procesos celulares, tales como: la diferenciación celular, la progresión del ciclo celular, el desarrollo y la apoptosis celular. Existen varios tipos de proteasomas como el constitutivo, los intermedios, el inmunoproteasoma y el timoproteasoma, los cuales están presenten en las células del cuerpo en dependencia de la estructura y función de ellas. Sin embargo, se encuentran en las células del sistema inmune donde no solo juegan un papel muy importante en el procesamiento antigénico para la respuesta inmune, sino en los mecanismos de tolerancia central durante el proceso de ontogenia de los linfocitos T en el timo. Así, las células epiteliales tímicas corticales son células presentadoras de antígenos, las cuales presentan características intrínsecas únicas al presentar el timoproteasoma, la catepsina L y la proteasa serin específica del timo. Además, se ha observado una alta tasa de macroautofagia en comparación a las otras células del cuerpo, por lo que serán esenciales en la obtención de un repertorio de linfocitos T CD4+ y CD8+ que tendrán la capacidad de discriminar lo propio y lo no propio. Por lo que se debería considerar que la tolerancia central no está únicamente definida por el mecanismo de selección negativa, sino que a su vez la selección positiva juega un papel muy importante en la definición del repertorio de clones de linfocitos T no autorreactivos. El objetivo es discutir acerca del proteasoma, los tipos de proteasomas y sus implicaciones en la tolerancia central de los linfocitos T(AU)

The proteasome is a large protein complex mainly located in all eukaryote cells, where it plays a very important role in cellular processes like differentiation, cycle progression, development and apoptosis. There are several types of proteasomes: constitutive, intermediate, immunoproteasome and thymoproteasome, which are present in cells depending on their structure and functions. However, they are found in cells of the immune system, where they play a very important role not only in antigenic processes related to the immune response, but also in central tolerance mechanisms during T lymphocyte ontogeny in the thymus. Thymic cortical epithelial cells are therefore antigen-presenting cells with unique intrinsic characteristics, since they contain thymoproteasome, cathepsin L, and thymus-specific serine protease. Additionally, a high rate of macroautophagy has been observed in comparison with bibr cells of the body. They are thus essential to obtain a repertoire of CD4+ and CD8+ T lymphocytes capable of distinguishing the body's own elements from alien structures. Therefore, central tolerance should not be viewed as only defined by the negative selection mechanism, since positive selection also plays a very important role in defining the repertoire of non-autoreactive T lymphocyte clones. The purpose of the study was to discuss the proteasome, the types of proteasomes and their involvement in T lymphocyte central tolerance(AU)

The Role of Dendritic Cells in Central Tolerance

Dendritic cells (DCs) play a significant role in establishing self-tolerance through their ability to present self-antigens to developing T cells in the thymus. DCs are predominantly localized in the medullary region of thymus and present a broad range of self-antigens, which include tissue-restricted antigens expressed and transferred from medullary thymic epithelial cells, circulating antigens directly captured by thymic DCs through coticomedullary junction blood vessels, and peripheral tissue antigens captured and transported by peripheral tissue DCs homing to the thymus. When antigen-presenting DCs make a high affinity interaction with antigen-specific thymocytes, this interaction drives the interacting thymocytes to death, a process often referred to as negative selection, which fundamentally blocks the self-reactive thymocytes from differentiating into mature T cells. Alternatively, the interacting thymocytes differentiate into the regulatory T (Treg) cells, a distinct T cell subset with potent immune suppressive activities. The specific mechanisms by which thymic DCs differentiate Treg cells have been proposed by several laboratories. Here, we review the literatures that elucidate the contribution of thymic DCs to negative selection and Treg cell differentiation, and discusses its potential mechanisms and future directions.

Thymic Atrophy during Infection as a Host Response to Avoid Tolerance to Persistent Pathogens.

The immune system consists in part of a functionally competent T-cell repertoire that is reactive to foreign antigens but tolerant to self-antigens. The repertoire of T cells is primarily formed in the thymus through positive and negative selection of developing thymocytes that are critical for establishing central tolerance. One of the features of the thymus is to sense stress hormones produced in pathophysiological conditions. Increased levels of these hormones are associated with infections and are able to induce thymic atrophy. We have shown that in acute Trypanosoma cruzi infections, the atrophic thymus is a consequence of increased thymocyte apoptosis and premature export of immature thymocytes to secondary lymph nodes. This atrophy does not necessarily result in dysfunction of the thymus since the organ micro architecture is preserved and maintains negative selection, thus avoiding the development of tolerance to the pathogen during the establishment of protective immunity. However, in chronic infections, the dissemination of invading pathogens able to target the thymus interferes with T cell differentiation, generating T cells that are tolerant to pathogen-specific antigens. In what follows we propose to describe what is known about thymic atrophy induced by infectious pathogens in the context of host-pathogen interactions.