Thymus leukemia antigen controls intraepithelial lymphocyte function and inflammatory bowel disease

Abstract

Intestinal intraepithelial lymphocytes (IEL) bear a partially activated phenotype that permits them to rapidly respond to antigenic insults. However, this phenotype also implies that IEL must be highly controlled to prevent misdirected immune reactions. It has been suggested that IEL are regulated through the interaction of the CD8␣␣ homodimer with the thymus leukemia (TL) antigen expressed by intestinal epithelial cells. We have generated and characterized mice genetically-deficient in TL expression. Our findings show that TL expression has a critical role in maintaining IEL effector functions. Also, TL deficiency accelerated colitis in a genetic model of inflammatory bowel disease. These findings reveal an important regulatory role of TL in controlling IEL function and intestinal inflammation.CD8␣␣ ͉ mucosal immunity ͉ colitis ͉ nonclassical MHC ͉ immunoregulation T he intestinal mucosa represents one of the major entry points for antigens into the body, and thus requires a refined immunological system that can prevent the invasion and dissemination of both commensal and pathogenic microorganisms. One of the main immunological compartments involved in regulating mucosal immune responses is comprised by the intraepithelial lymphocytes (IEL). IEL are a population of lymphocytes that reside within the intestinal epithelium, and constitute one of the largest populations of lymphocytes in the body. In mice, 3 main subpopulations of IEL have been identified: TCR␥␦ ϩ T cells expressing mostly the CD8␣␣ homodimer, TCR␣␤ ϩ T cells expressing either CD4 or CD8␣␤ and sometimes coexpressing CD8␣␣, and TCR␣␤ ϩ T cells expressing CD8␣␣ (1). Many reports indicate that these populations function in the recognition of stress signals (2), are involved in the recovery from tissue damage (3, 4), function as conventional memory cells (1), or have natural autoreactivity, suggesting a regulatory role (5, 6). Despite their varied function and phenotype, the great majority of IEL are characterized by a ''partial activation'' state (7). This phenotype suggests that IEL are capable of rapidly responding to stimuli, and therefore, must be held in tight check to prevent unwanted reactions. Thus, an intriguing aspect is the regulation of the effector functions of IEL, which remains incompletely understood.The thymus leukemia (TL) antigen is a nonclassical MHC class I molecule encoded by a locus within the MHC complex (8). TL expression is confined to the surface of intestinal epithelial cells (IEC) (9, 10) and it does not appear to bind an antigenic moiety (11,12). Recently, it has been demonstrated that TL binds preferentially to the CD8␣␣ homodimer (11-17), and it has been suggested that this interaction, at least in vitro, modulates IEL responses.Considering that CD8␣␣ is a prevalent surface marker on IEL, and that these cells reside in close proximity to TL-expressing IEC, we hypothesized that TL has a key role in regulating IEL effector functions. In the present study, we have analyzed mice deficient in the expression of TL and report...

CD8αα + Innate-Type Lymphocytes in the Intestinal Epithelium Mediate Mucosal Immunity

“…We have previously shown that H2-T3 expression in IEC is dispensable for the development and maintenance of TCR + IEL expressing CD8α homodimers, the primary ligand for H2-T3 (Olivares-Villagomez et al, 2008). However, it has not been determined whether H2-T3 expression influences the cellularity and/or function of TCR − IEL.…”

“…CD8αα binds with high affinity to H2-T3 (also known as the thymus leukemia antigen or TL), an MHC class I-like molecule that lacks antigen-presenting properties (Liu et al, 2003; Old and Boyse, 1963; Weber et al, 2002). It has been proposed that the interaction of H2-T3 with CD8αα modulates IEL-mediated immune responses (Leishman et al, 2001; Olivares-Villagomez et al, 2011; Olivares-Villagomez et al, 2008). However, very little is known about TCR − lymphoid cells expressing CD8α homodimers within the intestinal epithelium.…”

Diverse developmental pathways of intestinal intraepithelial lymphocytes

“…It is possible that MHC class I reactivity is more important than MHC class II reactivity for the maintenance of the unconventional IEL pool in the intestinal epithelial layer. In that regard, by binding the non-classical mouse MHC class Ib molecule thymus leukaemia antigen (TL; also known as H2-T3), CD8αα may provide crucial signals to IELs in the intestinal epithelial layer, although TL-deficient mice did not have an obvious defect in the unconventional IEL populations 59,60 . Although more studies are required to better define the relevant MHC ligands of IELs in the thymus and intestinal environments, the expression of crossreactive TCRs indicates that IELs might be responding to broad changes in classical and non-classical MHC levels rather than to the presentation of particular peptides, a scenario reminiscent of signalling for NK cells.…”

Human MAIT and CD8αα cells develop from a pool of type-17 precommitted CD8+ T cells

“…In fact, mice that lack the CD8␣␣ ligand TL, which is constitutively expressed in the murine gut, develop a more severe phenotype of colitis in experimental models. 39 In humans CD8␣␣ is likely to play an analogous role, potentially imposing an important threshold to activation of these innate-like T cells, dampening activation on encounter with MR1 expressing cells. They may also play a role in determining the overall functional phenotype of the cells (eg, predominant IL-17 vs IL-22 production) depending of the type of activation or homeostatic signals received.…”