No abstract

SummaryMany body surfaces harbor organ-specific γδ T cell compartments that contribute to tissue integrity. Thus, murine dendritic epidermal T cells (DETCs) uniquely expressing T cell receptor (TCR)-Vγ5 chains protect from cutaneous carcinogens. The DETC repertoire is shaped by Skint1, a butyrophilin-like (Btnl) gene expressed specifically by thymic epithelial cells and suprabasal keratinocytes. However, the generality of this mechanism has remained opaque, since neither Skint1 nor DETCs are evolutionarily conserved. Here, Btnl1 expressed by murine enterocytes is shown to shape the local TCR-Vγ7+ γδ compartment. Uninfluenced by microbial or food antigens, this activity evokes the developmental selection of TCRαβ+ repertoires. Indeed, Btnl1 and Btnl6 jointly induce TCR-dependent responses specifically in intestinal Vγ7+ cells. Likewise, human gut epithelial cells express BTNL3 and BTNL8 that jointly induce selective TCR-dependent responses of human colonic Vγ4+ cells. Hence, a conserved mechanism emerges whereby epithelia use organ-specific BTNL/Btnl genes to shape local T cell compartments.

Objective. Recently, 2 classes of cytokine inhibitors have been defined at the molecular level. The largest group comprises the extracellular domains of cell surface cytokine receptors, and includes both tumor necrosis factor receptors (TNF-R). The present study was conducted to investigate the role of TNF inhibitors in arthritis.Methods. We measured p55 and p75 soluble TNF-R (sTNF-R) in serum and synovial fluid (SF)

In spite of their precipitous encounter with the environment, newborn infants cannot readily mount T helper type 1 (TH1) cell antibacterial and antiviral responses. Instead, they show skewing toward TH2 responses, which, together with immunoregulatory functions, are thought to limit the potential for inflammatory damage, while simultaneously permitting intestinal colonization by commensals. However, these collective capabilities account for relatively few T cells. Here we demonstrate that a major T cell effector function in human newborns is interleukin-8 (CXCL8) production, which has the potential to activate antimicrobial neutrophils and γδ T cells. CXCL8 production was provoked by antigen receptor engagement of T cells that are distinct from those few cells producing TH1, TH2 and TH17 cytokines, was co-stimulated by Toll-like receptor signaling, and was readily apparent in preterm babies, particularly those experiencing neonatal infections and severe pathology. By contrast, CXCL8-producing T cells were rare in adults, and no equivalent function was evident in neonatal mice. CXCL8 production counters the widely held view that T lymphocytes in very early life are intrinsically anti-inflammatory, with implications for immune monitoring, immune interventions (including vaccination) and immunopathologies. It also emphasizes qualitative distinctions between infants' and adults' immune systems.

Acknowledgement of the breadth of T-cell pleiotropy has provoked increasing interest in the degree to which functional responsiveness is elicited by environmental cues versus differentiation. This is particularly relevant for young animals requiring rapid responses to acute environmental exposure. In young mice, cd T cells are disproportionately important for immuno-protection. To examine the situation in humans, we compared populations and clones of T cells from term and preterm babies, and adults. By comparison with ab T cells, neonate-derived cd cells show stronger, pleiotropic functional responsiveness, and lack signatory deficits in IFN-c production. Emphasising the acquisition of functional competence in utero, IFN-c was produced by cd cells sampled from premature births, and, although one month's post-partum environmental exposure invariably increased their TNF-a production, it had no consistent effect on IFN-c or IL-2. In sum, cd cells seem well positioned at birth to contribute to immuno-protection and immuno-regulation, possibly compensating for selective immaturity in the ab compartment. With regard to the susceptibilities of preterm babies to viral infection, cd cells from preterm neonates were commonly impaired in Toll-like receptor-3 and -7 expression and compared with cells from term babies failed to optimise cytokine production in response to coincident TCR and TLR agonists. Key words: Neonate immunity . gd T cells . Toll-like receptors Supporting Information available online IntroductionAfter the protected intra-uterine environment, birth exposes the newborn mammal to precipitous encounter with antigens. Although several groups have concluded that lymphocytes from young animals can, under optimal conditions, successfully mount robust immune responses [1][2][3], it is also clear de facto that immune responses in children and young animals are sub-optimal and that neonates and infants are more vulnerable to infections, and respond less well to most vaccines than do older children or adults [4][5][6]. While different studies primarily attribute the problem to intrinsic defects in à These authors contributed equally to this work. 1794T cells or APC, respectively, it is likely that both are impaired in vivo [7].One particularly striking deficit reported in neonatal ab T cells is in IFN-g production, which underpins Th1 responses to intracellular parasites, bacteria and certain viruses. Such defects in conventional T-cell responses have fuelled the hypothesis that gd T cells, that are relatively rare in the blood and lymphoid circulation of adults, may contribute disproportionately to immune function in the young. Supporting this, weanling gd cell-deficient (TCR-d À/À ) mice, relative to wild-type counterparts, show a delayed acquisition of immune resistance to the natural gut pathogen, Eimeria vermiformis ([8] and our unpublished data). There is a similar susceptibility of young TCR-d À/À mice to infection by Cryptosporidium [9]. Provocatively, very early T-cell development is disproportionately di...

The study of animal immune physiology and animal models of human disease have accelerated many aspects of translational research by allowing direct, definitive investigations. In particular, the use of mice has allowed genetic manipulation, adoptive transfer, immunization, and focused cell and tissue sampling, which would obviously be unthinkable for studies in humans. However, the disease relevance of some animal models may be uncertain and difficulties in interpretation may occur as a consequence of immunological differences between the two species. In this review, we will consider general differences in the structure and development of human and mouse mucosal lymphoid microenvironments and then discuss species differences in mucosal B- and T-cell biology that relate to the current concepts of intestinal immune function.

Levels of GZMA and ITGAE mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab; expression levels decrease with etrolizumab administration in biomarker(high) patients. Larger, prospective studies of markers are needed to assess their clinical value.

The Regulator of G Protein Signaling 1 [RGS1] gene is associated with celiac disease, multiple sclerosis (MS) and Type I diabetes (T1D), which are all T cell-mediated pathologies. And yet there is no reported analysis of RGS1 biology in human T cells. This study shows that RGS1 expression is substantially higher in T cells from human gut versus peripheral blood, and that this can be exaggerated in intestinal inflammation. Elevated RGS1 levels profoundly reduce T cell migration to lymphoid-homing chemokines, whereas RGS-1 depletion selectively enhances such chemotaxis in gut T cells, and impairs their colitogenic potential. These findings provide a revised framework in which to view the linkage of RGS1 to inflammatory disease.