The Development of Unconventional Extrathymic Activated CD4+CD8+T Cells in Chagas Disease

Alexandre Morrot

doi:10.5402/2013/801975

Abstract

The numbers of extrathymic CD4+CD8+double-positive (DP) T cells are augmented in various pathophysiological conditions, such as infectious diseases caused by intracellular pathogens, organs subjected to autoimmune attack and malignant tumors. The roles performed by extrathymic DP T cells are not clear, and it is not known how they are distributed in the body. In animals they have been considered memory cells involved in adaptive immune responses against virus infections or participating in pathological responses. In experimentalTrypanosoma cruziinfections, there is a severe thymic atrophy and this results in the release of activated DP T cells to peripheral organs. In severe cardiac forms of human chronic Chagas disease activated HLA-DR+DP T cells are present in the blood. In investigating the basis of premature thymocyte release during chagasic thymic atrophy we found that the parasitetrans-sialidase (TS) altered intrathymic thymocyte maturation and was associated with increased numbers of recent T cells in peripheral lymphoid organs. In what follows we propose to describe what is known about the origin of the extrathymic DP T cells in human Chagas disease and animal models of the disease.

Highlights

The formation of mature lineage-committed T cells requires the specialized environment of the thymus, whereas B cells generally develop while still in the bone marrow [1, 2]
The surviving thymocytes undergo in the medulla of the thymus a second, negative selection process, which leads programmed cell death of thymocytes whose T cell receptor (TCR) have an above-threshold affinity for self-peptide/major histocompatibility complex (MHC) complexes
It is clear that DP T cells are released prematurely from infected thymuses into the periphery, where their maturation into functionally competent single-positive cells continues [105] even though intrathymic checkpoints remain active in the acute phase of murine Chagas disease [53, 82]. This unconventional and rare (

Summary

T Cell Development in the Thymus

The formation of mature lineage-committed T cells requires the specialized environment of the thymus, whereas B cells generally develop while still in the bone marrow [1, 2]. After a time required for maturation, these naıve single-positive (SP) T cells (i.e., CD4−CD8+ and CD4+CD8− thymocytes) exit the thymic medulla and migrate to the periphery in a process that requires signaling via sphingosine 1-phosphate receptor type 1 [37, 38]. In this way, thymocyte development requires signals emanating from a number of different types of stromal cells, thymic epithelial cells (TEC); these influence their entry, division, maturation, and survival [39, 40]. The processes involved in TEC multiplication and maintenance have been extensively studied since the functioning of these cells is affected by aging and by anticancer treatments [41,42,43,44]

Infectious Diseases Can Result in Thymic Atrophy

Concluding Remarks