Frontline T cells: γδ T cells and intraepithelial lymphocytes (2007)

The fox knows many things, but the hedgehog knows one big thing. —Archilochus (7th century BC) If physicists are hedgehogs in their drive to achieve a unified field theory or a grand synthesis encompassing all the forces of nature, then certainly immunologists are foxes: they are splitters rather than synthesizers. With the power of multicolor flow cytometry and other methods, immunologists have divided the lymphocytes into ever more separate populations. Initially, all T cells were considered to be essentially the same. Of course CD4+ T cells recognize peptides presented by major histocompatibility complex (MHC) class II and CD8+ T cells recognize peptides presented by MHC class I, but in their positive selection by cortical thymic epithelial cells, their thymic negative selection, and their behavior as mature cells, CD4+ and CD8+ T cells probably are more similar than different. Many years ago this simple dichotomy of the T-cell world gave way to an increasing diversity of T-cell subpopulations. Broadly speaking, these unconventional T-cell populations have several things in common, although there are exceptions. First, they are not necessarily restricted by MHC class I or class II molecules, and they need not express either of the T-cell coreceptors, CD4 or CD8αβ, although they can express them. Second, they tend to have an activated or memory phenotype, and they are to varying extents self-reactive. Their activated phenotype is correlated with the ability to rapidly display effector function after activation. This rapid effector response is reminiscent of the rapid responses of innate immune cells. Third, their differentiation pathways are different from conventional T cells, and their distinct differentiation pathways imprint their distinct phenotypes and behaviors. Fourth, they tend to be a minority population in the typical locations that lymphocytes reside in, such as spleen and lymph nodes, although they may be more concentrated in other sites including epithelia and the liver. This volume contains articles that analyze two of these unconventional populations, giving an overview of the state-of-the-art research in these areas. Ten reviews consider those T cells that express a γδ T-cell antigen receptor (TCR) in mice and humans. The δ gene locus was originally cloned by subtractive hybridization in a search for the TCR α locus 1, but biochemical and immunochemical work established these cells as a separate lineage 2. The γδ T cells are not necessarily a unitary population, as some data, particularly from studies in mice, suggest that the epithelial trophic γδ T cells are quite different from those in the circulation. Three reviews consider aspects of the development of γδ T cells. One describes the genes required for γδ T-cell development 3, and another analyzes the role of morphogens, such as members of the Wnt signaling pathway, in deciding the αβ versus γδ lineage choice 4. In the mouse, γδ T cells develop in waves, with skin-seeking dendritic epidermal T cells expressing an invariant Vγ3Vδ1 TCR developing first 5. Xiong and Raulet 6 discuss the role of TCR gene expression in determining the nature of these waves, and they consider the experimental evidence for and against the positive selection of γδ T cells. It should be noted that authors use different nomenclatures for Vγ gene segments. For example, the Vγ3 segment in Xiong and Raulet 6 is referred to as Vγ5 elsewhere, for example, in Nanno et al.7. Three other reviews describe the specificity of γδ T cells, which has been enigmatic. Chien and Konigshofer 8 describe elegant studies of the interaction of some mouse γδTCRs with MHC class II and non-classical class I molecules. Morita et al.9 discuss the recognition of several types of self-ligands and foreign small molecules recognized by the major population of circulating human γδ T cells, which express a Vγ2Vδ2 TCR [elsewhere referred to as Vγ9Vδ2, as in Moser and Eberl 10]. It remains to be determined, however, if these small molecules require presentation. O’Brien et al.11 describe promising experimental data using TCR multimers to detect cell types potentially expressing ligands for γδTCRs. This technology may allow the identification of some of the ligands for the invariant as well as the more variable mouse γδTCRs, which have long been elusive. Four reviews assess the function of γδ T cells. Moser and Eberl 10 describe the unique pattern of chemokine receptor expression by circulating human γδ T cells, and they show that these cells can have antigen-presenting function. Nanno et al.7 review data indicating that mouse γδ T cells can have an anti-inflammatory effect in a graft-versus-host disease model and a parasitic infection model, while their roles in several colitis models are more complex. Jameson and Havran 12 discuss evidence that intraepithelial γδ T cells in mouse skin play unique roles in tissue homeostasis and during tissue repair through the production of particular growth factors. Thedrez et al.13 provide a discussion of innate features of γδ T cells that distinguish them from αβ T cells and allow discrimination of healthy from diseased cells. Excitingly, these features are being exploited for new immunotherapeutic strategies for the treatment of malignancies. Nine contributions discuss intraepithelial lymphocytes (IELs) of the intestine of mice and humans. In mice, many IELs express CD8αα homodimers in the absence of either the CD4 or CD8αβ TCR coreceptors. These unconventional CD8αα cells can express either a γδTCR or an αβTCR. Therefore, while mouse IELs are predominantly CD8+, they contain mixtures of conventional and unconventional T lymphocytes. Kunisawa et al.14 provide a comprehensive introduction to these different IEL populations. Three articles reexamine the long-standing controversy regarding the thymic dependence of the CD8αα+ cells, which recently has been reinvestigated using new tools. Ishikawa et al.15 describe the cryptopatches, which contain clusters of cells in intestinal crypts, some of which can have T-cell precursor function, while Rocha 16 emphasizes the results from thymus-grafting experiments indicating that immature, double-negative thymocytes can exit the thymus and undergo maturation in the intestine. By contrast, Lambolez et al.17 describe recent studies showing a thymic origin for the CD8αα+ cells that express an αβTCR. Their data suggest that these cells arise from a novel CD4+ CD8αβ+ thymocyte subset that coexpresses CD8αα. Collectively, the data from the different groups show that the CD8αα+ IELs can have either a thymic or an extrathymic origin, depending on the experimental circumstances, and therefore the critical issue now is to determine which pathway is normally dominant in vivo. The fate-mapping experiments of Eberl and Littman 18 probably involve the least experimental manipulation, and they clearly favor a double-positive precursor for the TCRαβ+ CD8αα+ IEL, but the controversy is likely to continue. Johansson-Lindbom and Agace 19 discuss how the chemokine receptor CCR9 and the integrin α4β7 are uniquely important for the generation of different populations of conventional and unconventional mucosal T cells, including IELs, in the small but not large intestine. Subsets of dendritic cells have been characterized that can impart the expression of these intestine-homing molecules by activated T cells and thereby impart a gut-seeking behavior. Montufar-Solis et al.20 discuss the partially activated phenotype of IELs and how different costimulatory molecules of the tumor necrosis factor and immunoglobulin families, as well as other molecules such as transforming growth factor-β, regulate their responses. Jabri and Ebert 21 discuss the dominance of the CD8αβ+ population in human IELs and emphasize their similarity with CD8 effectors elsewhere in the periphery, in contrast to the prevalence of the unconventional IELs in mice. They consider how inhibitory and activating natural killer receptors regulate the responses of human IELs, a feature they apparently share in common with mouse IELs. Probert et al.22 provide a summary of the TCR repertoire studies that have been carried out on IELs. These cells are surprisingly oligoclonal in both mice and humans, and inflammatory bowel disease further shapes the TCR repertoire. This oligoclonality only arises after birth, however, suggesting that it is shaped by antigenic drive. Dahan et al.23 recount how intestine epithelial cells influence mucosal T cells in the epithelium and lamina propria and vice versa. Mucosal lymphocytes can influence epithelial turnover, while the epithelium can induce a suppressed or regulatory state in human CD8+ T cells. In their study of these unusual T lymphocytes, the articles in this volume touch on almost every area of modern immunology research, from detailed biochemical studies of antigen recognition to complex disease models. Despite the application of the very best tools and great progress, clearly much remains to be learned about the functions of γδ T cells and IELs. It is worth noting too that there are yet other populations of unconventional T lymphocytes that share some of the features of the populations considered here, including a lack of requirement for MHC class I or class II reactivity, aberrant patterns of coreceptor expression, a unique developmental pathway, self-reactivity, an activated phenotype, and rapid effector function. These lymphocytes include CD1d-dependent invariant natural killer T cells and MR1-reactive mucosa-associated invariant T cells. Discussion of these cells is beyond the scope of this volume. Although sometimes the different unconventional populations, including those discussed in this volume, have been ignored, they are ignored at the peril of the investigator, because collectively these different T-cell subsets have been shown to have a profound effect on a variety of immune responses.