Thymocyte death by neglect: Contribution of engulfing macrophages

Abstract

The thymus provides the microenvironment in which thymocytes develop into mature T cells, and interactions with thymic stromal cells are thought to provide the necessary signals for thymocyte maturation. Recognition of self-MHC by T cells is a basic requirement for mature T-cell functions, and those thymocytes that do not recognize the peptide-loaded self-MHC molecules found in the thymus, and therefore lack a TCR signal, undergo a default death pathway named "death by neglect" in the thymic cortex. In the absence of this TCR signaling, it has been suggested that binding of glucocorticoids toor the ligation of certain cell surface molecules, such as CD8, CD24, CD45, or CD99 on -these neglected thymocytes will induce them to enter the apoptotic program. Apoptotic thymocytes are cleared by the surrounding macrophages and, as a consequence, these macrophages are known to release various molecules, such as adenosine, retinoids, TGF-β, ATP, and carbon monoxide. Interestingly, all these molecules have been described to induce or promote apoptosis in thymocytes in the absence of TCR signaling. Here, we propose that thymic macrophages, because they continually engulf apoptotic cells, might constantly provide these cell death-inducing signals, and thus contribute to the formation of a thymic milieu that ensures the effective induction of "death by neglect".

Transcriptional control of transglutaminase 2 expression in mouse apoptotic thymocytes

“…Those thymocytes that are not able to create the preTCR undergo apoptosis is thought to be induced by the BH3 only Bcl-2 family proteins Bim and Bid (Szondy et al, 2012).…”

“…The expression of Mcl-1 is continuous during thymocyte development, Bcl-xL -induced by retinoid-related orphan receptor (ROR)-γ -is specifically expressed on DP thymocytes, while express low levels of the antiapoptotic Bcl-2, due to a failure in IL-7 signaling (Szondy et al, 2012). The low level of Bcl-2 ensures, that these cells are more susceptible to apoptosis, which is needed for the proper selection of selfreacting thymocytes.…”

“…However, 90% of the DP thymocytes that are incapable of recognizing self-peptides presented on major histocompatibility complex (MHC) molecules present in the thymus undergo a default death pathway named "death by neglect" (Chung et al, 2002;Szondy et al, 2012).The mechanism is unclear, but it has been proposed that, (1) in the absence of TCR signaling, binding of glucocorticoids (produced by TECs or the adrenal cortex), via the mitochondrial pathway involving Bcl-2 family members (Veis et al, 1993), especially via Puma and Bim (Erlacher et al, 2006;Villunger et al, 2003), or (2) the crosslinking of various cell surface receptors (such as CD8, CD24, CD45) will induce the cell death program in the neglected DP cell population.…”

“…In addition, DP cells are also affected by glucocorticoids and retinoids produced by MHC presenting thymic epithelial cells. All of these contribute to the formation of the proapoptotic thymic milieu that ensures the induction of apoptosis of neglected thymocytes in the absence of TCR signaling (Chung et al, 2002;Szondy et al, 2003;Szondy et al, 2012).…”

A tobozmirigy-csecsemőmirigy rendszer szerepe az autoimmunitás, öregedés és élettartam szabályozásában

“…Az autoreaktív immunsejtek a thymusban kapnak olyan jelzést, amely miatt még itt öngyilkosságot követnek el (apoptózis), vagy ha mégis kijutnak a perifé-ÖSSZEFOGLALÓ KÖZLEMÉNY riára, ott pusztulnak el. A csontvelőből a thymusba bejutó lymphoid sejtek 95%-a semmisül meg, és csak 5% nem kapja meg a "halálos csókot" (markert), amely a véget jelenti [8].…”