br Gut Damage in Conditions Other Than
Gut Damage in Conditions Other Than HIV: Learning From “Outside the Box” Early in the HIV pandemic, GI dysfunctions were reported in patients progressing to AIDS. These dysfunctions included nutrient malabsorption, diarrhea and weight loss, all of which pointed to a link between the disruption of immune homeostasis and gut damage (Kotler et al., 1984). Initial descriptions of the pathological changes observed in patients with advanced HIV infection evoked GI manifestations of Crohn\'s disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD), (Ho et al., 2014). Both IBD and HIV infections can be considered as conditions involving a breakage in the mutualism between the host and the gut microbiota. Graft-versus-host disease (GVHD) is also characterized by features of gut damage including immunosuppression, alteration of the composition of the intestinal microbiota, and microbial translocation, all of which lead to systemic inflammation (Jenq et al., 2012).
Gut Damage in SIV Infection: A Mucosal Tragedy
Strategies to Restore the Integrity of the Gut Barrier
Search Strategy and Selection Criteria
Funding This review article was supported by the Canadian Institutes of Health Research (grant MOP #103230 and CTN #257), and by FRQ-S: Therapie cellulaire, Réseau SIDA/Maladies Infectieuses, Québec.
Introduction Similar to solid organs, T Caspase-6, human recombinant protein have been suggested to harbour a self-renewing stem cell-like population which permanently replenishes the pools of further differentiated effectors. Since central memory T (TCM) cells have been shown to repopulate the effector memory T (TEM) cell and effector T (TEFF) cell pools in response to antigen stimulus (Graef et al., 2014; Wherry et al., 2003), they were thus far regarded as “memory stem cells”. However, further complexity was brought to this view by the recent discovery of an additional memory T cell subset, which was able to mediate a prolonged immune response in a mouse model of graft-versus-host disease (GVHD) (Zhang et al., 2005). This memory T cell subset, termed stem cell-like memory T (TSCM) cells, has been recently described in mice, non-human primates and in humans (Gattinoni et al., 2009, 2011; Lugli et al., 2013). As least differentiated distinct memory T cell subset, TSCM cells have been put at the top of the hierarchy of all memory T cell subsets in a model of progressive T cell differentiation, leading from naive T (TN) cells over TSCM cells and TCM cells to TEM cells and TEFF cells. This position of TSCM cells between TN cells and memory T cells is phenotypically reflected by the expression of activation markers as the death receptor CD95, the β-chain of the IL-2 receptor (CD122) or the adhesion molecule CD58 on naive-appearing CCR7+, CD45RA+, CD45RO− T cells (Gattinoni et al., 2011). After genetic modification into mesothelioma-specific CAR T cells, adoptively transferred TSCM cells were shown to mediate an improved anti-tumour immune response compared to TN cells, TCM cells and TEM cells in a humanized mouse model (Gattinoni et al., 2011), which seems to depend on a more efficient TSCM cell engraftment and long-term persistence in the host which enables them, while self-renewing, to constantly differentiate into TEFF cells and, thereby, to completely eradicate the tumour. Because of these ideal characteristics there is a quest for the signalling pathways which mediate TSCM cell induction. Once identified, pharmacological interference with these signalling pathways could be used for their targeted induction in anti-tumour immunotherapy. In this regard, the in vitro activation of CD8+ TN cells in the presence of the Wnt-β-catenin (short: Wnt) signalling pathway activator TWS119, which inhibits glycogen synthase kinase-3β (GSK-3β) by phosphorylation, has been suggested to arrest TN cell differentiation and to generate TSCM cells (Gattinoni et al., 2011). However, the interpretability of these data remains inconclusive, since the starting pool of TN cells also contained TSCM cells so that an expansion effect of TWS119 on pre-existing TSCM cells or TSCM cell self-maintaining factors cannot be excluded. Moreover, increasing evidence suggests that T cell metabolism is an important determinant of T cell differentiation (Pearce et al., 2009), which raises the possibility that metabolic integrators like mechanistic/mammalian Target Of Rapamycin (mTOR) kinase might represent pharmacological targets for the enrichment of a desired differentiation-defined T cell population (Araki et al., 2009; Diken et al., 2013; Rao et al., 2010; Turner et al., 2011), thereby potentially favouring the induction of qualitatively improved memory T cells.