Comparative analysis of thymic subpopulations during different modes of atrophy identifies the reactive oxygen species scavenger, N‐acetyl cysteine, to increase the survival of thymocytes during infection‐induced and lipopolysaccharide‐induced thymic atrophy

Abstract

Summary The development of immunocompetent T cells entails a complex pathway of differentiation in the thymus. Thymic atrophy occurs with ageing and during conditions such as malnutrition, infections and cancer chemotherapy. The comparative changes in thymic subsets under different modes of thymic atrophy and the mechanisms involved are not well characterized. These aspects were investigated, using mice infected with Salmonella Typhimurium, injection with lipopolysaccharide (LPS), an inflammatory but non‐infectious stimulus, etoposide (Eto), a drug used to treat some cancers, and dexamethasone (Dex), a steroid used in some inflammatory diseases. The effects on the major subpopulations of thymocytes based on multicolour flow cytometry studies were, first, the CD4− CD8− double‐negative (DN) cells, mainly DN2–4, were reduced with infection, LPS and Eto treatment, but not with Dex. Second, the CD8+ CD3lo immature single‐positive cells (ISPs) were highly sensitive to infection, LPS and Eto, but not Dex. Third, treatment with LPS, Eto and Dex reduced all three subpopulations of CD4+ CD8+ double‐positive (DP) thymocytes, i.e. DP1, DP2 and DP3, but the DP3 subset was relatively more resistant during infection. Fourth, both CD4+ and CD8+ single‐positive (SP) thymocytes were lowered by Eto and Dex, but not during infection. Notably, LPS lowered CD4+ SP subsets, whereas the CD8+ SP subsets were relatively more resistant. Interestingly, the reactive oxygen species quencher, N‐acetyl cysteine, greatly improved the survival of thymocytes, especially DNs, ISPs and DPs, during infection and LPS treatment. The implications of these observations for the development of potential thymopoietic drugs are discussed.

Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses

“…Of particular interest is the observation that the thymus is remarkably sensitive to inflammation (e.g., sepsis or experimental LPS-induced thymic involution) and oxidative stress which leads to thymic involution that seems to be irreversible [79][80][81][82][83][84]. Deleterious pro-apoptotic effects on both thymus stromal cells and intrathymic T cells are underlying this phenomenon.…”

Age-related loss of intestinal barrier integrity plays an integral role in Thymic involution and T cell ageing

“…However, aged germ-free mice exhibited comparable IL6 expression levels to those in young wild-type mice, indicating a role for microbial translocation in the age-dependent upregulation of thymopoiesissuppressing cytokines. Indeed, LPS treatment and E. coli enterotoxin cause thymic atrophy, leading to the loss of single positive (CD4 − ve CD8 +ve and CD4 + ve CD8 −ve ) thymocytes as well as double positive (CD4 + ve CD8 +ve ) and double negative (CD4 − ve CD8 −ve ) thymocytes [57,58]. One mechanism by which this occurs is through LPS-induced apoptosis of thymocytes [59].…”

Thymus Subset Alterations Accompanying Concomitant Tumor Immunity Mimics Phenotypic Patterns of Cytotoxic Drug Doxorubicin

“…The signature of drug or tumorinduced rearrangements in the thymus might be significantly extended if multiple other immunophenotype characteristics are considered. For instance, the CD4+CD25+FOX3+ thymic subset in a rapamycin study (19) or CD25, CD44, CD24, CD5, and CD25 markers (20) were also explored as indicators of thymocyte toxicity. Some mechanisms of cortical thymocyte depletion might be specific to certain chemotherapeutic drug.…”

“…In fact, the cortical thymocyte is potentially the most fragile body cell being rapidly triggered to undergo programmed cell death in vivo and in vitro. Characteristic rearrangements detectable in certain thymocyte subsets as a specific signature of a drug can be ascribed to immunomodulating agents such as cyclosporin (17), doxorubicin (17,18), rapamycin (19), etoposide, lipopolysaccharide, dexamethasone (20), and some other (21).…”