Interleukin 15 controls the generation of the restricted T cell receptor repertoire of γδ intestinal intraepithelial lymphocytes

Abstract

AbstractγδT cells are prevalent in the mucosal epithelia and are postulated to act as sentries to maintain tissue integrity. What these γδT cells recognize is poorly defined, but based on the restricted T cell receptor (TCR) repertoire, the notion that they are selected by self-antigens of low complexity has been widely disseminated. We present data demonstrating that generation of the restricted TCR Vγ gene repertoire of intestinal intraepithelial lymphocytes is regulated by IL-15, which induces Vγ gene segmentspecific local chromatin modifications and enhanced accessibility conducive for subsequent targeted gene rearrangement. This cytokine-directed tissue-specific TCR repertoire formation likely reflects distinct TCR repertoire selection criteria for γδ and αβT cell lineages adopted for different antigen recognition strategies.Intestinal intraepithelial lymphocytes (i-IELs) found within the intestinal epithelial layer are an essential component of mucosal immunity. Similar to T cell subsets in other lymphoid tissues, i-IELs are composed of two T cell types, αβ and γδT cells. In contrast to other tissues, however, γδT cells are prevalent in the mucosal epithelia of most vertebrates and are thought to be a major source of secreted factors necessary for the maintenance of tissue integrity subsequent to infection, transformation, or cell injury 1-3 .Despite the long history of i-IELs, their origin and ligand specificity remain uncertain. Earlier work has indicated that αβ i-IELs originate exclusively from the thymus in normal mice 4 , but whether γδ i-IELs are subject to similar developmental constraints is unclear. The majority of human and mouse γδ i-IELs express the homodimeric αα form of the CD8 coreceptor and exhibit restricted Variable (V) γ and V δ gene usage. In C57BL/6 (B6) mice, for example, V γ 5 expressing cells constitute the predominant i-IEL population in the small intestine [5][6][7] . Mouse strain-specific preferential usage of Tcrg and Tcrd genes among i-IELs arises from complex molecular and cellular controls with evidence for genetic linkage to the Tcrg, Tcrd and H2 loci 6,8,9 , but the exact mechanism is unknown. Two non-mutually exclusive mechanistic processes can be considered to account for the restricted TCR gene usage: cellular selection and programmed TCR gene rearrangement. A hallmark of adaptive immunity is the cellular selection process geared toward forming a population of cells with antigen receptor repertoires that can recognize the entire external universe of antigens. This selection pressure acts on immature cell subsets expressing randomly generated clonal antigen receptors. Although the TCR-driven selection shaping the αβTCR repertoire of conventional αβT cells constitutes a fundamental theme in immunology, whether a similar process is needed for γδT cell development, and specifically for γδ i-IELs, remains a matter of debate [10][11][12] .

IL-15 Does Not Affect IEL Development in the Thymus but Regulates Homeostasis of Putative Precursors and Mature CD8αα+ IELs in the Intestine

“…In this study, ATXBM chimera engrafted with either WT or Il15ra Ϫ/Ϫ thymus generated similar results to an earlier study by Schluns et al (8) ϩ ␥␦ iIEL of WT recipients but were preferentially reduced in Il15ra Ϫ/Ϫ recipients. This observation is consistent with a later study reporting that IL-15 differentially promotes rearrangement of the V␥5 locus (31). In this study, we found that Il15ra Ϫ/Ϫ thymus is able to restore Thy1 Ϫ V␥5 ϩ CD8␣␣ ϩ iIEL to WT level in nude mice, implying that the IL-15-promoted V␥5 rearrangement in iIEL precursors occurs outside of the thymus and thus favors the model that CD8␣␣ ϩ iIEL precursors exit the thymus before TCR rearrangement and colonize the intestine to generate CD8␣␣ ϩ ␥␦ iIEL (15).…”

Intra- and Intercompartmental Movement of γδ T Cells: Intestinal Intraepithelial and Peripheral γδ T Cells Represent Exclusive Nonoverlapping Populations with Distinct Migration Characteristics

“…We hypothesized that mouse epithelial or keratinocyte cell lines could replace such cell-cell contacts, and may provide a microenvironment that supports gd iIEL survival ex vivo. To test this hypothesis, we cocultured GFP high gd iIELs either with the intestinal epithelial cell line m-IC (cl2) or with the keratinocyte cell line PDV for a period of 7 d. Furthermore, GFP high gd iIELs were cultured with a mixture of the cytokines IL-2, IL-7, and IL-15, which have been reported to at least slightly prolong the ex vivo life span of isolated gd iIELs (26,27,(53)(54)(55)(56)(57). By FACS quantification of GFP + cells it quickly became evident that m-IC (cl2) cells were not supporting the ex vivo survival of sorted gd iIELs (Fig.…”

Interleukin-15 Is Critical in the Pathogenesis of Influenza A Virus-Induced Acute Lung Injury

“…IL-15 utilizes the ␤-chain of the IL-2 receptor (IL-2R) (CD122) and the common cytokine receptor ␥-chain (CD132) for signal transduction in lymphocytes and therefore shares many biological properties with IL-2 (3). Memory CD8 ϩ T cells, natural killer (NK) cells, NKT cells, and intraepithelial lymphocyte (IEL) T cells (15,23,42) decrease in mice with defective IL-15 signaling, indicating the importance of IL-15 in their development and/or maintenance. IL-15 regulates not only the number of memory CD8…”