Apoptosis signaling pathways and lymphocyte homeostasis

It has been almost three decades since the term ＂apoptosis＂ was first coined to describe a unique form of cell death that involves orderly, gene-dependent cell disintegration. It is now well accepted that apoptosis is an essential life process for metazoan animals and is critical for the formation and function of tissues and organs. In the adult mammalian body, apoptosis is especially important for proper functioning of the immune system. In recent years, along with the rapid advancement of molecular and cellular biology, great progress has been made in understanding the mechanisms leading to apoptosis. It is generally accepted that there are two major pathways ofapoptotic cell death induction： extrin- sic signaling through death receptors that leads to the formation of the death-inducing signaling complex （DISC）, and intrinsic signaling mainly through mitochondria which leads to the formation of the apoptosome. Formation of the DISC or apoptosome, respectively, activates initiator and common effector caspases that execute the apoptosis process. In the immune system, both pathways operate; however, it is not known whether they are sufficient to maintain lymphocyte homeostasis. Recently, new apoptotic mechanisms including caspase-independent pathways and granzyme-initiated pathways have been shown to exist in lymphocytes. This review will summarize our understanding of the mechanisms that control the homeostasis of various lymphocyte populations.

Homeostasis of T Cell Diversity

T cell homeostasis commonly refers to the maintenance of relatively stable T cell numbers in the peripheral lymphoid organs.Among the large numbers of T cells in the periphery,T cells exhibit structural diversity,i.e.,the expression of a diverse repertoire of T cell receptors(TCRs),and functional diversity,i.e.,the presence of T cells at nave,effector,and memory developmental stages.Although the homeostasis of T cell numbers has been extensively studied,investigation of the mechanisms underlying the maintenance of structural and functional diversity of T ceils is still at an early stage.The fundamental feature throughout T cell development is the interaction between the TCR and either self or foreign peptides in association with MHC molecules.In this review,we present evidence showing that homeostasis of T cell number and diversity is mediated through competition for limiting resources. The number of T cells is maintained through competition for limiting cytokines,whereas the diversity of T cells is maintained by competition for self-peptide-MHC complexes.In other words,diversity of the self-peptide repertoire limits the structural(TCR)diversity of a T cell population.We speculate that cognate low affinity self-peptides, acting as weak agonists and antagonists,regulate the homeostasis of T cell diversity whereas non-cognate or null peptides which are extremely abundant for any given TCR,may contribute to the homeostasis of T cell number by providing survival signals.Moreover,self-peptides and cytokines may form specialized niches for the regulation of T cell homeostasis.Cellular & Molecular Immunology.2005;2(1):1-10.

An orally administered bacterial membrane protein nanodrug ameliorates doxorubicin cardiotoxicity through alleviating impaired intestinal barrier

The cardiotoxicity caused by Dox chemotherapy represents a significant limitation to its clinical application and is a major cause of late death in patients undergoing chemotherapy.Currently,there are no effective treatments available.Our analysis of 295 clinical samples from 132 chemotherapy patients and 163 individuals undergoing physical examination revealed a strong positive correlation between intestinal barrier injury and the development of cardiotoxicity in chemotherapy patients.We developed a novel orally available and intestinal targeting protein nanodrug by assembling membrane protein Amuc_1100(obtained from intestinal bacteria Akkermansia muciniphila),fluorinated polyetherimide,and hyaluronic acid.The protein nanodrug demonstrated favorable stability against hydrolysis compared with free Amuc_1100.The in vivo results demonstrated that the protein nanodrug can alleviate Dox-induced cardiac toxicity by improving gut microbiota,increasing the proportion of short-chain fatty acid-producing bacteria from the Lachnospiraceae family,and further enhancing the levels of butyrate and pentanoic acids,ultimately regulating the homeostasis repair of lymphocytes in the spleen and heart.Therefore,we believe that the integrity of the intestinal barrier plays an important role in the development of chemotherapy-induced cardiotoxicity.Protective interventions targeting the intestinal barrier may hold promise as a general clinical treatment regimen for reducing Dox-induced cardiotoxicity.