Regulatory T cells and inflammatory bowel disease.

Recent studies have identified interleukin 10 as a differentiation factor for a novel subset of immune suppressive regulatory T cells. Here, Hervé Groux and Fiona Powrie discuss the role that these cells play in the regulation of immune responses to enteric antigens and suggest that a deficiency in these cells might be involved in the pathogenesis of inflammatory bowel disease.     

Increase of circulating gamma/delta T lymphocytes in the peripheral blood of patients affected by active inflammatory bowel disease.

In order to study the role of gamma/delta T cells in the pathogenesis of inflammatory bowel disease (IBD) in humans, we measured the percentage of these cells in the peripheral blood, assessed the ratio of the non-disulphide-linked (delta TCS1) type of T cell receptor (TCR) in the total gamma/delta T cells, studied the co-expression of gamma/delta TCR and accessory molecules CD8 and CD16, and compared these data with both the type and the activity of the disease. Percentage levels and absolute numbers of gamma/delta+ T cells were higher in active patients than in controls (P < 0.05), mainly as a result of an increase of V delta 1+ (delta TCS1) T cell subset (P < 0.05). This trend was strongly retained independently of disease activity and clinical picture. An increased percentage of TCR delta 1+/CD16+ cells was observed in our patients compared with controls (P < 0.05). In contrast, no difference was observed as far as the TCR delta 1+/CD8+ cells were concerned. These results suggest that IBD is associated with an expansion of gamma/delta T cells in peripheral blood, which may play a role in the pathogenesis of these disorders.     

Chagas' disease is attenuated in mice lacking gamma delta T cells.

The role of gamma delta T cells in the immunopathology of Chagas' disease is evaluated by monitoring the course of Trypanosoma cruzi infection in mice lacking gamma delta T cells after disruption of the T-cell receptor C delta locus. Levels of parasitemia, states of lymphocyte activation, and levels of lymphokine production as well as tissue pathology are compared in delta knockout mice and their littermates in acute and chronic phases of infection. Although the levels of circulating parasites do not significantly differ in the two groups, mortality scores and numbers of inflammatory lesions of skeletal and cardiac muscles are lower in gamma delta T cell-deficient m ice than in littermate controls. Furthermore, polyclonal lymphocyte activation, as measured by proliferative activities and numbers of B- and T-cell blasts in the spleen, are reduced in deficient mice in the acute and chronic phases of infection. Levels of gamma interferon mRNA obtained from total spleen cells, known to be a critical lymphokine in resistance to T. cruzi infection, are significantly higher in uninfected gamma delta T cell-deficient mice than in control animals and slightly above levels for littermates in the course of acute infection. Interestingly, however, in chronic phases, the levels of this lymphokine are not statistically different between the two groups of mice. These results indicate that gamma delta T cells do not play a crucial role in parasite clearance during the acute phase of the disease but contribute to the mechanisms leading to tissue damage and pathology.     

gamma delta T cells in autoimmunity

Conclusions  γδ T cells likely play a critical role in the host defenses, and recent evidence has indicated they are important in regulation of the immune response after pathogen challenge. Data are also accumulating that they play a part in autoimmunity and immune regulation. Evidence indicates that γδ T cells mediate these effects through cytokine production, via direct effects on cells of the adaptive immune response, or through interactions with innate immune components or barriers. Nevertheless, the biological function of γδ T cells in immune responses, especially in autoimmunity, largely remains unresolved. Further studies are needed to gain more knowledge about the immunobiology of these cells, asking why precisely they bear an activated phenotype in vivo, how their cytokine production is regulated, and how they interact with other cells of the innate and adaptive immune responses.     

Biology of murine gamma delta T cells.

Murine lymphocytes express either a T-cell receptor alpha beta or a gamma delta heterodimer. The function of alpha beta cells are well characterized, while gamma delta cells remain an enigmatic population. In the mouse, gamma delta cells appear in significant proportions in the epithelia of various nonlymphoid tissues such as the skin, intestine, tongue, lung, and reproductive organs. While gamma delta T-cell subsets with distinct antigen receptor repertoires are associated with certain organs, diversified populations of gamma delta cells showing heterogeneous TCR phenotypes, as a result of junctional region diversification and usage of different V chains, can be found in the lymphoid organs and in the intestinal epithelia. Recent evidence has shown that gamma delta cells might recognize heat shock proteins, possibly in association with classical and nonpolymorphic MHC molecules. Together with their tissue distribution, gamma delta cells may represent the first line of defense of the immune system. gamma delta Cells are the first T cells to colonize the thymus. Intriguingly, there is more evidence to support the hypothesis that they might also affect the development of alpha beta cells and other hematopoietic stem cells.     

Human T cell receptor gamma delta + T cells.

TCR gamma delta + T cells represent a minority of CD3+ T cells in many species including man. The molecular structure of the TCR gamma and delta loci in man is well understood. The gamma and delta loci contain V, D, J and C gene segments. These segments do not rearrange randomly but in a coordinated, ordered fashion during thymic development. Therefore, the structure of gamma and delta genes of early fetal TCR gamma delta + thymocytes differ drastically from those in postnatal TCR gamma delta + thymocytes. In contrast to postnatal TCR gamma delta + thymocytes, early fetal-TCR gamma delta + produce substantial levels of IL-4 and IL-5 and the possibility is discussed that the early fetal TCR gamma delta + cells are involved in development of TCR gamma delta + cells. In man, unlike in mouse, no preferential homing of early fetal TCR gamma delta + cells has been observed so far. Mature human peripheral TCR gamma delta + cells can recognize a great variety of cell surface antigens including 'classical' and 'non-classical' MHC antigens, immunoglobulins and other undefined antigens. In addition, TCR gamma delta + can recognize bacterial products. So far, no class of antigens has been defined that is preferentially recognized by TCR gamma delta + T cells and the function of these cells remains elusive.     

Analysis of gamma delta T cells in the chicken.

T cell development in birds and mammals is remarkably similar. One hallmark of these similarities is the division of T cells into two sublineages characterized by different T cell receptor (TCR) molecules--the gamma delta and alpha beta TCRs. These two sublineages differ in several ways besides the molecular form of the TCR, such as the mechanisms involved in TCR repertoire selection and their pattern of tissue localization. The extensive similarity between the avian and mammalian gamma delta T cells suggest that the separation of these two lineages is relatively ancient evolutionarily. The advantages of the avian system as a developmental model have allowed information to be obtained on the gamma delta T cells which may be of general relevance.     

Development and selection of gamma delta T cells.

The gamma delta T-cell population, a subpopulation of T cells formed through cell lineages that are independent of the alpha beta T-cell lineage, consists of multiple subsets with distinct receptor repertoires and homing properties. While the cell sublineage is a critical factor in the determination of homing specificity, both cell sublineage and receptor-dependent selection are instrumental in the determination of the functional repertoire.     

Specificity of gamma delta receptor bearing T cells.

T cells expressing the gamma delta receptor heterodimer can recognize a broad array of different antigens, including classical and non-classical major histocompatibility complex (MHC) proteins, MHC-like CD1 antigens, and bacterial antigens such as the mycobacterial heat shock proteins and staphylococcal enterotoxins. Reactivity to self antigens including autologous stress proteins implicates TCR gamma delta T cells in autoimmune disease. It is as yet unclear whether the responses of gamma delta T cells specific for soluble proteins are restricted by conventional or non-classical MHC molecules. Correlations of TCR gamma delta usage with specificity suggest that, like TCR alpha beta, sequences encoded within both the V regions and the V(D)J junctions are important in determining receptor specificity.     

Environmental influences on T regulatory cells in inflammatory bowel disease

Inflammatory bowel disease (IBD) is characterized by chronic, idiopathic inflammation of the intestine. The disease is thought to result from a combination of genetic and environmental factors which ultimately leads to a mucosal immune system that overreacts to normal constituents of the mucosal microbiota. The inflammation in IBD is primarily mediated by inappropriate production of proinflammatory cytokines by CD4(+) T effector cells, effects that are suppressed by CD4(+) T regulatory cells. Defects in both the function of T regulatory cells, and the ability of T effector cells to be suppressed, have been implicated in IBD. In this review we will discuss environmental factors, including cytokines, vitamins A and D, and commensal bacteria, which influence the phenotype and function of regulatory T cells and thereby alter the course of IBD. We will also discuss how these environmental signals can be manipulated therapeutically in order to improve the function of regulatory T cells and ultimately restore mucosal homeostasis in patients with IBD.     

Positive selection of gamma delta T cells

The issue of T-cell repertoire selection has been addressed recently by several laboratories. While evidence has been provided for both negative and positive selection of CD4+ and CD8+ alpha beta T cells, the molecular basis of positive selection remains unclear. In this article Juan Lafaille and colleagues describe molecular features of gamma delta T-cell selection in the fetal thymus. These features were deduced from extensive junctional sequence data of gamma delta T-cell receptor genes in fetal thymocytes. Their data suggest the active participation of a self peptide in the positive selection of gamma delta T cells.     

Involvement of gamma delta T cells in immunity to trypanosomiasis.

In this study the involvement of peripheral gamma delta T cells, prepared by flow cytometry, in the immune response of cattle to primary infection with Trypanosoma congolense was assessed. Negligible in vitro proliferative responses were observed in gamma delta T cells isolated from trypanosusceptible Boran (Bos indicus) cattle at all stages examined post-infection when stimulated in vitro with parasite antigens. In contrast, both CD8+ T cells and gamma delta T cells from trypanotolerant N'Dama (Bos taurus) cattle proliferated markedly when stimulated in vitro with a complex of invariant trypanosome antigens with MW between 100,000 and 140,000 (100,000 MW complex). Neither species of cattle exhibited significant T-cell recognition of trypanosome variable surface glycoprotein (VSG). To study further the functional and phenotypic characteristics of the gamma delta T-cell response, four T-cell lines were established from infected N'Dama cattle. These cell lines were comprised of up to 96% gamma delta (WC1+) T cells, the remainder being CD8+ T cells. Two of these gamma delta T-cell lines exhibited 100,000 MW complex antigen specificity which was not major histocompatibility complex (MHC) restricted in one line.     

Epithelial and mucosal gamma delta T cells

Although they constitute a small part of the circulating lymphocyte population, gammadelta T cells are found in high abundance on mucosal and epithelial surfaces. These gammadelta T cells are activated in response to stress to the surrounding tissue and perform a number of functions depending upon the location and type of stress that has occurred. Roles elucidated recently for gammadelta T cells include modulation of epithelial homeostasis through insulin-like growth factor-1 and keratinocyte growth factor, lysis of cytomegalovirus-infected cells, and recruitment of inflammatory cells to sites of tissue damage. Recent advances have provided an understanding of the development of mucosal and skin gammadelta T cells and their roles in restoring and maintaining tissue integrity.     

Epithelial defence by gamma delta T cells

Gamma delta T cells constitute a separate lineage of T lymphocytes which differ from conventional alpha beta T cells with regard to T cell receptor (TCR) repertoire and tissue localization. In murine skin, gamma delta T cells expressing a canonical V gamma5 TCR are abundant and contribute as so-called dendritic epidermal T cells to local immune surveillance. In humans, major subsets of gammadelta T cells are recognized on the basis of their TCR V delta usage. While V delta2 cells dominate in the peripheral blood, V delta1 cells are preferentially localized in mucosal tissue including the intestinal epithelia. In this article we summarize basic features of intraepithelial gamma delta T cells and discuss their possible role in epithelial defence.     

Alteration in T lymphocyte subpopulations in inflammatory bowel disease.

Peripheral blood mononuclear cells from thirty-one patients with inflammatory bowel disease (ulcerative colitis and Crohn's disease) were analysed for the proportions and absolute numbers of total T cells, and for the T cell subpopulations carrying Fc receptors for either IgM (Tmu cells) or IgG (T gamma cells). Twenty-six control subjects were studied simultaneously. Total T cell numbers were normal in patients with inflammatory bowel disease but there was a marked reduction in the proportion and absolute numbers of Tmu cells in patients, whether their disease was active or in remission. T gamma cells were normal. Simultaneous assessment of lymphocyte response to mitogens in vitro was performed in a group of patients. Responses to phytohaemagglutinin, concanavalin A and pokeweed mitogen were decreased and a positive correlation was found between the number of circulating Tmu cells and the responses to mitogens in vitro. These studies demonstrate that despite the presence of normal numbers of total T cells in inflammatory bowel disease, there is a marked imbalance in T cell subpopulations that correlates with mitogen responsiveness. This imbalance provides a possible cellular basis for the defect in cell-mediated immunity seen in these patients.     

The immunobiology of gamma delta+ T cells

T cells expressing the gd receptor are the major lymphocyte type represented in intraepithelial layers of various organs in the mouse. The gd cells found in distinct anatomical locations express distinct restricted subsets of Vg and Vd genes. Cells in each site are probably derived from progressive intrathymic waves of gd cells expressing these restricted V gene subsets. These features of the cells suggest a role in monitoring epithelial layers for distinctive ligands, and recent studies implicate mycobacterial "stress proteins' as antigens for g/d T cells. Thus gd T cells may represent an arm of the immune system devoted to elimination of infected, transformed or otherwise stressed autologous epithelial cells, based on recognition of induced stress proteins. They may also be devoted to mycobacterial immunity by virtue of specificity for mycobacterial stress proteins and other antigens.     

A novel multi-gene family of sheep gamma delta T cells.

The WC1 protein is a cell surface constituent of bovine gamma delta T cells and is absent from most or all CD4+, CD8+ T cells and from B cells. It is a single polypeptide chain of 1413 amino acids consisting of 11 non-identical repeats of a 110 amino acid consensus sequence, homologous to the macrophage scavenger receptor cysteine rich (SRCR) domain. A 1059 nucleotide segment of the bovine WC1 cDNA sequence was used as a probe to molecularly clone homologous DNA segments from a sheep genomic library in which the presence of numerous positive plaques was documented. The high representation of such recombinants (1-2/1000 clones) within the library suggested the existence of multiple genes for WC1 (called T19 in sheep) and supported Southern blotting data which revealed an unexpectedly high number of WC1/T19 restriction fragments in sheep genomic DNA. Restriction digests of 27 samples of T19 genomic recombinants were examined by electrophoresis and Southern blotting. All but two pairs of recombinants exhibited non-overlapping restriction digest patterns. Four recombinant DNA samples were partially sequenced and in all cases putative exons were identified and exhibited high homology to appropriate segments of the WC1 cDNA at the levels of both nucleotide and amino acid sequence. Furthermore, multiple nucleotide and amino acid differences occurred between all sequences compared, establishing the existence of a repertoire of non-identical T19 genes, each with the potential to encode a different protein.     

Functionally distinct subsets of human gamma/delta T cells.

To determine if effector subsets exist among human gamma/delta T cells, we examined the cytokine production and cytotoxic activity of gamma/delta T cell clones with different accessory molecule phenotypes, V delta and V gamma gene expression, and J gamma rearrangements. T cell clones bearing gamma/delta T cell receptor produce an array of cytokines like alpha/beta T cell clones. Individual gamma/delta T cell clones produced a characteristic array of cytokines without correlation with V delta or V gamma gene expression. However, when phenotypic subsets were considered, CD4+ gamma/delta clones produced significantly higher levels of interleukin 2 and granulocyte-monocyte colony-stimulating factor compared with CD4-CD8- and CD8+ gamma/delta clones. Similarly, when cytotoxic potential was assessed, CD4+ gamma/delta clones exhibited minimal activity when compared with CD4-CD8- and CD8+ adult peripheral blood gamma/delta clones. We conclude that functionally distinct gamma/delta T cell subsets exist and suggest that these subsets may correlate with expression of the CD4 accessory molecule.