Tolerance has its limits: how the thymus copes with infection

Abstract

The thymus is required for T cell differentiation; a process that depends on which antigens are encountered by thymocytes, the environment surrounding the differentiating cells, and the thymic architecture. These features are altered by local infection of the thymus and by the inflammatory mediators that accompany systemic infection. Although once believed to be an immune privileged site, it is now known that antimicrobial responses are recruited to the thymus. Resolving infection in the thymus is important because chronic persistence of microbes impairs the differentiation of pathogen-specific T cells and diminishes resistance to infection. Understanding how these mechanisms contribute to disease susceptibility, particularly in infants with developing T cell repertoires, requires further investigation.

Keywords: T cell repertoire; antimicrobial response; infection; thymic microenvironment; thymus.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Figure 1. T cell differentiation

Schematic representation of T cell traffic within the thymus and location of the major steps during T cell selection. T cell precursors from the bone marrow enter the thymus in the cortico-medullary region and migrate to the cortex, where they go through the double negative (DN; e.g., CD4-CD8-) stages of T cell differentiation and become double positive (DP; e.g., CD4+CD8+) cells. DP cells migrate from the cortex to the medulla, interacting with structural components of the thymus in these regions during positive and negative selection. The resulting naive single positive (SP; e.g., CD4+CD8- or CD4-CD8+) cells exit the thymus and migrate to the peripheral lymphoid organs. Several microbes can be detected within the thymus following infection. Examples of microbes that are detected in the cortex, medulla or cortico-medullary region of the thymus following in vivo infection are shown. DC, dendritic cell; DN, double negative thymocytes; DP, double positive thymocytes; SP, single positive thymocytes; cTEC, cortical thymic epithelial cell; mTEC, medullary thymic epithelial cell.

Figure 2. The effects of infection on the thymus

Schematic representation of how infection can affect the thymus through systemic and/or local effects. Glucocorticoids and/or pro-inflammatory mediators mediate systemic effects, while local effects require the presence of a pathogen within the thymus. Infection-induced alterations include thymic atrophy, modifications in the thymic structure, and alterations in the T cells exported to the periphery. Representative pathogens capable of inducing the different alterations in thymic structure and/or function are indicated. DN – double negative thymocytes. DP – double positive thymocytes.

Figure 3. Immune response in the thymus

Schematic representation of microbial dissemination and recruitment of an immune response to the thymus. Under normal conditions, mature T cells and DC circulate from peripheral lymphoid organs to the thymus (left panel). Following infection, pathogens disseminate from the periphery to the thymus, either extracellularly or within re-circulating cells. The infected thymus produces chemokines, such as CXCL9 and CXCL10, which recruit CXCR3-expressing antigen-specific T cells from the peripheral tissues back to the thymus to fight infection (right panel). LN – lymph node.