Aggravation of intestinal inflammation by depletion/deficiency of gammadelta T cells in different types of IBD animal models

The role of gammadelta T cells in inflammatory bowel disease (IBD) is still controversial. Although gammadelta T cells induce IBD in immunodeficient animals, others suggest a protective role of gammadelta T cells. Therefore, this study was conducted in order to elucidate the effect of gammadelta T cell depletion/deficiency on different IBD animal models. Mice depleted of or deficient in gammadelta T cells were exposed to dextran sodium sulfate (DSS) in order to induce colitis. In addition, gammadelta T cells were depleted in mice with terminal ileitis (TNFDeltaARE) or colitis due to interleukin 2 deficiency (IL-2 ko). Finally, DSS-induced colitis was studied in mice deficient in interferon gamma (IFN-gamma ko) upon gammadelta T cell depletion. Depletion of gammadelta T cells aggravated DSS-induced colitis and terminal ileitis of TNFDeltaARE mice. Exacerbated DSS-induced colitis was also found in gammadelta T cell-deficient mice. IL-2 ko mice showed increased mortality upon early (starting at 4 wk of age) but not late depletion (starting at 8 wk of age). Early gammadelta T cell depletion or deficiency resulted in increased IFN-gamma production by both lamina propria lymphocytes and splenocytes in every model investigated herein. In IFN-gamma ko mice, gammadelta T cell depletion did not affect the development and course of DSS-induced colitis. The protective effect of gammadelta T cells in IBD was confirmed in various IBD animal models. Particularly, during the early phase of intestinal inflammation, gammadelta T cells appear to be important. The mechanism seems to involve the control of IFN-gamma production and epithelial regeneration.     

Immunotherapy of inflammatory bowel diseases: current concepts and future perspectives

The etiology and the pathogenesis of inflammatory bowel diseases (IBD), e.g. Crohn's disease and ulcerative colitis are still not completely understood. However, there is growing evidence that an alteration of the mucosal immune system towards luminal antigens in a genetically susceptible host plays a key role in the pathogenesis of IBD. In particular, cytokines produced by intestinal epithelial cells, lamina propria macrophages and CD4+ T cells appear to contribute to the initiation and perpetuation of intestinal inflammation in IBD. This review focuses on the role of the mucosal immune system in the pathogenesis of IBD and potential novel immunotherapeutic strategies for chronic intestinal inflammation. Such strategies include recombinant antiinflammatory cytokines, neutralizing antibodies or fusion proteins, antisense oligonucleotides and adenoviral gene transfer.     

Inhibition of phosphoantigen-mediated gammadelta T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells

Tumour growth promotes the expansion of CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) which suppress various arms of immune responses and might therefore contribute to tumour immunosurveillance. In this study, we found an inverse correlation between circulating Treg frequencies and phosphoantigen-induced gammadelta T-cell proliferation in cancer patients, which prompted us to address the role of Tregs in controlling the gammadelta T-cell arm of innate immune responses. In vitro, human Treg-peripheral blood mononuclear cell (PBMC) co-cultures strongly inhibited phosphoantigen-induced proliferation of gammadelta T cells and depletion of Tregs restored the impaired phosphoantigen-induced gammadelta T-cell proliferation of cancer patients. Tregs did not suppress other effector functions of gammadelta T cells such as cytokine production or cytotoxicity. Our experiments indicate that Tregs do not mediate their suppressive activity via a cell-cell contact-dependent mechanism, but rather secrete a soluble non-proteinaceous factor, which is independent of known soluble factors interacting with amino acid depletion (e.g. arginase-diminished arginine and indolamine 2,3-dioxygenase-diminished tryptophan) or nitric oxide (NO) production. However, the proliferative activity of alphabeta T cells was not affected by this cell-cell contact-independent suppressive activity induced by Tregs. In conclusion, these findings indicate a potential new mechanism by which Tregs can specifically suppress gammadelta T cells and highlight the strategy of combining Treg inhibition with subsequent gammadelta T-cell activation to enhance gammadelta T cell-mediated immunotherapy.     

The role of gammadelta T cells in induction of bacterial antigen-specific protective CD8+ cytotoxic T cells in immune response against the intracellular bacteria Listeria monocytogenes.

The role of T-cell receptor (TCR) gammadelta T cells in the induction of protective TCR alphabeta T cells against infection by the intracellular bacteria Listeria monocytogenes was analysed. We found that depletion of gammadelta T cells by anti-TCR delta monoclonal antibody treatment before intravenous immunization of mice with a sublethal dose of viable L. monocytogenes resulted in reduction of protection against secondary challenge infection in the immunized mice. The gammadelta T-cell depletion also reduced induction of protective alphabeta T cells capable of transferring the protection against challenge infection of L. monocytogenes into naive mice. Furthermore, the protective T cells that were affected by the gammadelta T-cell depletion were suggested to be CD8+ cytotoxic T cells rather than CD4+ T cells by the following observations. First, induction of cytotoxic T lymphocytes specific to a L. monocytogenes-derived H-2Kd-restricted peptide (listeriolysin O 91-99) was significantly suppressed by gammadelta T-cell depletion before immunization. Second, gammadelta T-cell depletion did not affect cytokine production and proliferation of T cells from immunized mice in response to in vitro stimulation with heat-killed Listeria which preferentially stimulates CD4+ T cells. Third, CD8+ alphabeta T cells from control immunized mice transferred protection against infection of L. monocytogenes into naive mice but only a limited degree of protection was transferred by CD8+ T cells from the gammadelta T-cell-depleted immunized mice; and fourth, CD4+ alphabeta T cells from the gammadelta T-cell-depleted mice transferred a similar level of protection as those from the control immunized mice. All these results suggest that gammadelta T cells participate in establishment of protective immunity against intracellular bacteria by supporting priming of bacterial antigen-specific CD8+ cytotoxic T cells.     

Colitis-associated cancer: the role of T cells in tumor development

Chronic inflammation severely increases the risk for cancer development as seen in patients with inflammatory bowel disease (IBD). Although the exact mechanisms of inflammation-associated tumor development remain to be shown, a role for the adaptive immune system has been implicated in colitis-associated cancer (CAC). In fact, CD4+ effector T cells, which promote chronic inflammation in IBD, create a tumor convenient environment, which can lead to cancer initiation, promotion, and progression. Thereby, the cytokines interleukin-6 and tumor necrosis factor-α constitute an important link between inflammation and tumor growth. Furthermore, cytotoxic CD8+ T cells, which usually are protective as part of the host antitumor immune response in sporadic cancer, can contribute to the aggravation of chronic inflammation and thereby support tumor development. In contrast, regulatory T cells, which have been shown to attenuate tumor immunosurveillance, act as potent suppressors of chronic inflammation and thus can have protective effects in CAC. This review discusses the role of the adaptive immune response and especially T cells in the pathogenesis CAC and possible implications for the therapeutic applications.     

Workshop cluster 1+ gammadelta T-cell receptor T cells from calves express high levels of interferon-gamma in response to stimulation with interleukin-12 and -18

Gammadelta T-cell receptor(+) T lymphocytes are an important element of the innate immune system. Early production of interferon (IFN)-gamma by gammadelta T cells may have a role in linking innate and adaptive immune responses and contribute to T helper-1 bias. We investigated the role of cytokines in the activation and induction of IFN-gamma secretion by bovine workshop cluster 1(+) (WC1(+)) gammadelta T cells. The effects of culture with interleukin (IL)-12, IL-18, IL-15 and IL-2 were investigated; these cytokines are known to influence murine and human gammadelta T cells. We report that bovine WC1(+)gammadelta T cells are synergistically stimulated by IL-12 and IL-18 to secrete large quantities of IFN-gamma. Neonatal calves were shown to have significantly higher numbers of circulating WC1(+)gammadelta T cells than adult animals. In addition, the response of peripheral blood WC1(+)gammadelta T cells was significantly higher in neonatal calves compared with adult animals. However, in adult animals the response of lymph node WC1(+)gammadelta T cells to IL-12/IL-18 was more pronounced than that of peripheral blood WC1(+)gammadelta T cells. We hypothesize that the induction of IFN-gamma secretion from WC1(+)gammadelta T cells by IL-12 and IL-18 is likely to be an important element of the innate response to pathogens such as Mycobacterium bovis. The high numbers of WC1(+)gammadelta T cells in neonatal calves, and their inherent ability to respond to inflammatory cytokines, could be a key factor in the enhanced responses seen in calves to BCG vaccination.     

Human Vgamma9Vdelta2 T cells: promising new leads for immunotherapy of infections and tumors

Vgamma9Vdelta2 T cells, a major human peripheral gammadelta T-cell subset, react in vitro against a wide array of microbial agents and tumor cells. This broad reactivity pattern is conferred by non-peptidic phosphorylated isoprenoid pathway metabolites, referred to as phosphoantigens, which are able to specifically activate this gammadelta T-cell subset in a T-cell receptor dependent fashion. Recent studies provide new insights into the mode of action of phosphoantigens on Vgamma9Vdelta2 T cells and might explain how their recognition can allow detection of infected or altered self by the immune system. The broad antimicrobial and antitumoral reactivity of Vgamma9Vdelta2 T cells, their ability to produce inflammatory cytokines involved in protective immunity against intracellular pathogens and tumors, and their strong cytolytic and bactericidal activities suggest a direct involvement in immune control of cancers and infections. These observations have recently aided development of novel immunotherapeutic approaches aimed at Vgamma9Vdelta2 T-cell activation, which have already yielded encouraging results.     

The Th17 Cell Population and the Immune Homeostasis of the Gastrointestinal Tract

Th17 cells are a recently discovered subset of CD4⁺ T lymphocytes filling a hole in the repertoire of effector T cells. Th17 cells produce multiple cytokines, with pivotal impact on immune homeostasis, inflammation, and influencing a wide range of intestinal cell targets. The current issue of the International Reviews of Immunology is entirely dedicated to the various roles of Th17 T cells in the immune homeostasis and inflammation occurring in the gut. In addition to describing diverse Th17-mediated molecular pathways, a specific focus is being given to Th17 cell plasticity. This enables the Th17 cells to shift towards a Th1 profile, or to express IL-22, a protective cytokine in experimental colitis. Participation of microbiota-specific Th17 cells to normal immune homeostasis, and their role in the pathogenesis of inflammatory bowel disease (IBD), or of gluten specific-Th17 cells in celiac disease, are also being discussed. Neutralizing antibodies against IL-17A and IL-17F have commenced clinical testing in IBD. In conclusion, Th17 cells emerge as a key immune cell population and further elucidation of their roles and functional plasticity are warranted to support the discovery of novel therapies against IBD and other intestinal disorders.     

Small heat shock protein CRYAB inhibits intestinal mucosal inflammatory responses and protects barrier integrity through suppressing IKKβ activity

Alpha B-crystallin (CRYAB) is an important member of the small heat shock protein family, and plays a protective and therapeutic role in neurological inflammation. CRYAB expression was assessed in cultured HT29 and Caco-2 cells and inflamed mucosa of patients with inflammatory bowel disease (IBD) and colitis models in mice. Lentivirus-overexpressing and CRSIPR/Cas9 systems were used in different cells to upregulate and silence CRYAB expression, respectively. Cell permeable recombined fusion protein TAT-CRYAB was injected intraperitoneally into dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice to assess its anti-inflammatory effects. CRYAB was found to be significantly decreased in the inflamed mucosa from IBD patients and DSS-induced colitis in mice, and negatively correlated with the levels of TNF-α and IL-6, respectively. Enforced expression of CRYAB suppressed expression of proinflammatory cytokines (e.g., TNF-α, IL-6, IL-1β, and IL-8) via inhibiting the IKK complex formation, whereas lack of CRYAB expression markedly enhanced proinflammatory responses. Consistently, administration of TAT-CRYAB fusion protein significantly alleviated DSS- or TNBS-induced colitis in mice and protected intestinal barrier integrity. CRYAB regulates inflammatory response in intestinal mucosa by inhibiting IKKβ-mediated signaling and may serve as a novel therapeutic approach in the treatment of IBD.     

Th17 cells: interactions with predisposing factors in the immunopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory state of the GI tract of unknown etiology. Classically, tissue injury in IBD is thought to be primarily mediated by Th1 cells in Crohn's disease or Th2 cells in ulcerative colitis. The discoveries of new subsets of T-helper cells, especially Th17 cells, have revolutionized our understanding of the disease immunopathology. Th17 cells seem to affect both innate and adaptive immune responses by the release of regulatory cytokines. Understanding the role of Th17 cells in IBD pathogenesis and targeting their regulatory cytokines may provide potential therapeutic approaches for the treatment of IBD in the future.     

Human gingiva‐derived mesenchymal stem cells alleviate inflammatory bowel disease via IL‐10 signalling‐dependent modulation of immune cells

Current evidence indicates that inflammatory bowel disease (IBD) is caused primarily by impaired mucosal immunity, resulting in an imbalance between epithelial barrier function and tissue inflammation. Human gingiva‐derived mesenchymal stem cells (GMSCs) exhibit immunomodulatory and anti‐inflammatory effects in a variety of immunity‐ and inflammation‐associated diseases. However, the role of GMSCs in treating IBD has not been elucidated. Our study, therefore, examined the therapeutic effect and mechanism of GMSCs in a murine colitis model of IBD. Our results indicate that the infusion of GMSCs significantly prolonged survival and relieved symptoms. Phenotype analyses showed that the frequencies of NK1.1⁺ and CD11b⁺ cells, as well as CD4 T cells in the spleen, were suppressed in GMSC‐treated mice compared with the PBS‐ or fibroblast‐treated control groups. Additionally, GMSC treatment markedly increased the numbers of interleukin (IL)‐10⁺ regulatory T cells, reduced the secretion of pro‐inflammatory cytokines, and increased production of anti‐inflammatory cytokines. A mechanistic study revealed that anti‐IL‐10R antibody abolished the protective effect of GMSCs compared with mice treated with anti‐IgG antibody. Thus, our results indicate that GMSCs play a critical role in alleviating colitis by modulating inflammatory immune cells via IL‐10 signalling.     

V gamma 9V delta 2 T cells in human legionellosis

In humans, expansion of circulating Vgamma9Vdelta2 T cells seems to be a pathophysiological denominator shared by protozoan and intracellular bacterial diseases. The assumption was tested here on legionellosis, a condition conforming to the category but not yet described with respect to gammadelta T cells. Levels of Vgamma9Vdelta2 T cells in peripheral blood were measured at various intervals in 14 subjects undergoing a Pontiac fever-like disease, shown by serological investigation to be caused by Legionella micdadei. In samples obtained 4 to 6 days after the onset of the disease, the mean percentage (+/- the standard deviation) of Vgamma9Vdelta2+ T cells among CD3+ cells was 1.0% +/- 0.5%, compared to 5.0% +/- 3.9% in healthy control subjects (P < 0.001). Thereafter, a pronounced increase occurred and at 2 to 7 weeks after onset, mean peak levels were as high as approximately equal to 15%. During the next 6 months, values slowly declined, although without reaching the normal range. Percentages of gammadelta+ T cells expressing tumor necrosis factor alpha or gamma interferon in response to phorbol myristate acetate were assayed in vitro. At 14 to 16 days after the onset of disease, the expression of both cytokines was increased (P < 0.01), whereas at 5 to 7 weeks, the expression of tumor necrosis factor alpha was decreased (P < 0.05), possibly reflecting modulation of an inflammatory response. In conclusion, Pontiac fever was found to be associated with a pronounced and long-lasting expansion of Vgamma9Vdelta2 T cells, implying that the subset may also be pathophysiologically important in a mild and transient form of intracellular bacterial diseases. Surprisingly, the expansion was preceded by a depletion of circulatory Vgamma9Vdelta2 T cells. Possibly, Vgamma9Vdelta2 T cells are initially recruited to a site of infection before they expand in response to antigen and occur in high numbers in blood.     

Immunotherapy against invasive fungal diseases in stem cell transplant recipients

Despite the availability of new antifungal compounds, morbidity and mortality of invasive fungal disease in allogeneic hematopoietic stem cell recipients are still unacceptably high. Over the past decade, one could witness an exciting improvement of the understanding of the molecular pathogenesis and of the complexity of host antifungal immune responses. This, in turn, provides critical information to augment host immunity against fungal pathogens. Strategies for enhancing the immune system include the administration of effector and regulatory cells (e.g., granulocytes, antigen-specific T cells, dendritic cells) as well as the administration of recombinant cytokines, interferons and growth factors (e.g., interferon-γ, keratinocyte growth factor, granulocyte- and granulocyte-macrophage colony stimulating factor). One has to recognize at the same time, however, that data of in vitro assays and animal models cannot necessarily be transferred into the clinical setting. In addition, meaningful clinical trials in allogeneic stem cell recipients suffering from invasive fungal disease require sufficiently large and homogenous cohorts of patients and can only be performed in international collaboration, but may ultimately improve the outcome of allogeneic transplant recipients with invasive fungal disease.     

Expression of CD45RB functionally distinguishes intestinal T lymphocytes in inflammatory bowel disease

The importance of CD45RB expression on T cells was already shown in mice where CD45RB(high) expression determines pathogenic potential. In this study, we analyzed the expression of CD45RA, CD45RB, and CD45RO on CD4(+) T lymphocytes in the intestinal mucosa and in the circulation of patients with inflammatory bowel disease (IBD). In addition, we studied the cytokine profile of these cells. In the circulation, virtually all CD4(+)CD45RB(high) T cells expressed the naive marker CD45RA, and circulating CD4(+)CD45RB(low) cells expressed the memory marker CD45RO in IBD patients and a control patient population. In contrast, the intestinal CD4(+) CD45RB(high) T cells are in normal controls for 90% CD45RO(+). However, in IBD, 27.7% [Crohn's disease (CD)] and 49% [ulcerative colitis (UC)] of the intestinal CD4(+) CD45RB(high) T cells are CD45RA(+). This special CD4CD45RA(+) T cell in IBD can be found in the lamina propria as well as in lymphoid follicles (confocal laser-scanning microscopy). The CD4(+)CD45RB(high) T lymphocytes produce significantly less interleukin (IL)-10 and IL-4 and produce more tumor necrosis factor alpha than CD45RB(low) T lymphocytes in control patients. CD4(+)CD45RB(low) T cells from IBD patients produced less IL-10 than CD4(+)CD45RB(low) T lymphocytes of controls, and interferon-gamma production by both T lymphocyte subsets was decreased in IBD. These data indicate that CD and UC are characterized by an influx of CD4(+)CD45RB(high) T lymphocytes. These CD4(+)CD45RB(high) T lymphocytes seem to be important in the pathogenesis of IBD, as they produce more proinflammatory cytokines and less anti-inflammatory cytokines compared with CD4(+)CD45RB(low) T lymphocytes.     

Th17 cells: interactions with predisposing factors in the immunopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory state of the GI tract of unknown etiology. Classically, tissue injury in IBD is thought to be primarily mediated by Th1 cells in Crohn’s disease or Th2 cells in ulcerative colitis. The discoveries of new subsets of T-helper cells, especially Th17 cells, have revolutionized our understanding of the disease immunopathology. Th17 cells seem to affect both innate and adaptive immune responses by the release of regulatory cytokines. Understanding the role of Th17 cells in IBD pathogenesis and targeting their regulatory cytokines may provide potential therapeutic approaches for the treatment of IBD in the future.     

Immunotherapy Against Invasive Fungal Diseases in Stem Cell Transplant Recipients

Despite the availability of new antifungal compounds, morbidity and mortality of invasive fungal disease in allogeneic hematopoietic stem cell recipients are still unacceptably high. Over the past decade, one could witness an exciting improvement of the understanding of the molecular pathogenesis and of the complexity of host antifungal immune responses. This, in turn, provides critical information to augment host immunity against fungal pathogens. Strategies for enhancing the immune system include the administration of effector and regulatory cells (e.g., granulocytes, antigen-specific T cells, dendritic cells) as well as the administration of recombinant cytokines, interferons and growth factors (e.g., interferon-γ, keratinocyte growth factor, granulocyte- and granulocyte-macrophage colony stimulating factor). One has to recognize at the same time, however, that data of in vitro assays and animal models cannot necessarily be transferred into the clinical setting. In addition, meaningful clinical trials in allogeneic stem cell recipients suffering from invasive fungal disease require sufficiently large and homogenous cohorts of patients and can only be performed in international collaboration, but may ultimately improve the outcome of allogeneic transplant recipients with invasive fungal disease.     

CD8+ cells suppress oil-induced arthritis

Oil-induced arthritis is a genetically restricted polyarthritis that develops in the DA rat after injection of the mineral oil Freund's incomplete adjuvant. Here, we investigated the role of the potentially disease-limiting cell populations CD8+ T cells, gammadelta T cells, natural killer (NK) cells and NK T cells in inguinal lymph nodes for the development of this adjuvant-induced arthritis. Flow cytometry analysis before and at disease onset revealed a higher proportion of lymph node T cells expressing NKR-P1 in the disease-resistant LEW.1AV1 compared with the disease-susceptible DA strain, suggesting that NK T cells might be disease protective. However, prophylactic in vivo administration of an anti-NKR-P1 MoAb (clone 10/78) did not consistently affect the disease course. The proportion of CD8+ T cells and the ratio CD4+/CD8+ T cells in inguinal lymph nodes did not differ significantly between DA and LEW.1AV1 rats before or at disease onset. Nevertheless, prophylactic in vivo depletion of CD8+ cells by the OX8 MoAb in the DA strain resulted in an earlier disease onset compared with the control group, demonstrating that CD8+ cells regulate arthritis development. In vivo depletion of gammadelta T cells by the V65 MoAb did not alter the disease course, indicating that the disease-suppressive CD8+ cells are alphabeta T cells or NK cells.     

TH1/TH2,3 Imbalance due to Cytokine-Producing NK, γδ T and NK-γδ T Cells in Murine Pregnancy Decidua in Success or Failure of Pregnancy

PROBLEM: Recurrent spontaneous abortion in DBA/2-mated CBA/J mice has been attributed to the production of Th1 cytokines (tumor necrosis factor [TNF]-alpha and interferon [IFN]-gamma) by asialoGM1+ natural killer (NK) cells and Vgamma1.1delta6.3+ T cells that infiltrate decidua by day 6.5, during the peri-implantation period. Abortions can be prevented by a second population of Vgamma1.1delta6.3 cells, which infiltrate on day 8.5 of gestation, and produce the Th2 cytokine interleukin (IL)-10 and Th3 cytokine transforming growth factor (TGF)-beta2. In low abortion rate immunocompetent mice, most of the TGF-beta2 is derived from gammadelta T cells. However, TGF-beta2-producing cells are present in the decidua of pregnant severe combined immune deficient (SCID) mice, which lack gammadelta T cells. METHODS: The cells in day 13.5 decidua of CBA x DBA/2 matings and SCID x SCID matings were identified using flow cytometry and combined surface staining for gammadelta and/or asialoGM1, and intracellular cytokine staining for TNF-alpha, IFN-gamma, and TGF-beta2,3. RESULTS: TGF-beta2 and TNF-alpha were found in asialoGM1+ NK cells in SCID mouse decidua. In CBA x DBA/2 mated mice, two major and one minor subsets of cytokine-positive cells were identified: -gammadelta-only T cells, double positive asialoGM1+ gammadelta+ (NK-gammadelta T) cells, and a small number of asialoGM1 +gammadelta- NK-only cells. The NK-only and NK-gammadelta T subsets showed a greater Th1/Th2,3 pattern of intracellular staining compared with the gammadelta-only subset. In the CBA x DBA/2 and SCID x SCID systems, Th1/Th2,3 ratios could not predict actual observed abortion rates but did correlate with susceptibility to abortions (if exposed to an additional stimulus such as stress). The known effect of in vivo administration of anti-asialoGM1 antibody on abortion rates within groups of mice exposed to such stresses could also be predicted. CONCLUSION: gammadelta+ cells in decidua (e.g. Vgamma1+ cells which can recognize trophoblasts) differ based on the presence or absence of the NK marker-asialo-GM1. NK-gammadelta T cells may be quite important in the Th1 response in early pregnancy that predisposes to abortions in CBA x DBA/2 matings, whereas gammadelta T-only cells appear to be protective. In pregnant SCID mice, the TNF-alpha+/TGF-beta2+ NK population is greatly expanded. An activating stimulus (such as stress or endotoxin) appears to be as important in triggering abortions, as is the Th1/Th2,3 ratio at the feto maternal interface.     

Differential expression of beta 2-integrins and cytokine production between gammadelta and alphabeta T cells in experimental autoimmune encephalomyelitis

The expression of beta 2-integrins on gammadelta T cells in na?ve mice or those with experimental autoimmune encephalomyelitis (EAE) remains poorly characterized. We compared beta 2-integrin expression and cytokine production between gammadelta and alphabeta T cells over the acute course of EAE. We observed that unlike in alphabeta T cells, beta 2-integrin expression on gammadelta T cells increased significantly from baseline, peaked at Day 10, and remained unchanged in the draining lymph nodes or declined in the spleen and CNS by Day 15. In addition, IFN-gamma- and TNF-alpha-producing gammadelta T cells infiltrated the CNS rapidly and produced significantly more of these cytokines than alphabeta T cells throughout the course of EAE. These results suggest unique roles for beta 2-integrins in the trafficking of gammadelta versus alphabeta T cells during EAE and that gammadelta T cells infiltrate the CNS rapidly, producing cytokines, which modulate acute disease.