Apoptosis of Fashigh CD4+ Synovial T Cells by Borrelia- reactive Fas-ligandhigh γδ T Cells in Lyme Arthritis

111

γδ T cells have been shown to regulate immune responses associated with inflammation, but the mechanism of this regulation is largely unknown. Using the experimental autoimmune encephalomyelitis (EAE) model of the human CNS autoimmune disease multiple sclerosis, we demonstrate that γδ T cells are important regulators of CNS inflammation. This was shown using γδ T cell-deficient mice that were unable to recover from EAE. The chronic disease was accompanied by a prolonged presence of both macrophages and lymphocytes in the CNS. This extended inflammatory response was due to alterations in both cell proliferation and death. In mice lacking γδ T cells, proliferation of encephalitogenic T cells was 3-fold higher, and caspase activity, indicating apoptosis, was 2-fold lower compared with those in control mice recovering from EAE. γδ T cell-deficient mice reconstituted with wild-type γδ T cells recovered from EAE and resolved inflammation in the CNS, whereas mice reconstituted with Fas ligand-dysfunctional γδ T cells did not. Thus, γδ T cells regulate both inflammation in the CNS and disease recovery via Fas/Fas ligand-induced apoptosis of encephalitogenic T cells, and a quick resolution of inflammation in the CNS is essential to prevent permanent damage to the CNS resulting in chronic disease.

Section: Discussionsupporting

confidence: 72%

γδ T Cells Regulate the Extent and Duration of Inflammation in the Central Nervous System by a Fas Ligand-Dependent Mechanism

Ponomarev

Dittel

2005

111

“…Evidence supporting selective ␥␦ ϩ cell lysis of CD4 ϩ lymphocytes comes from studies in Lyme arthritis (26) and from CVB3-induced myocarditis (12). In the latter studies, ␥␦ ϩ cells directly killed differentiated Th2 cell lines through Fas-dependent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that only specific ␥␦ ϩ cell populations may participate in disease processes. How ␥␦ ϩ cells participate in disease is also complex, as both beneficial and detrimental roles have been attributed to these cells in various experimental models (23)(24)(25)(26). Previously, we have demonstrated that different subpopulations of ␥␦ ϩ T cells, based on their V␥/V␦ use, were activated in the resistant (C57BL/6) vs the susceptible (Bl.Tg.E␣) mouse strain following infection with CVB3, with V␥1 cells dominating in the former and V␥4 cells dominating in the latter strain.…”

mentioning

confidence: 99%

Vγ1+ T Cells Suppress and Vγ4+ T Cells Promote Susceptibility to Coxsackievirus B3-Induced Myocarditis in Mice

Huber

Graveline

Newell

et al. 2000

137

124

Coxsackievirus B3 infections of C57BL/6 mice, which express the MHC class II IA but not IE Ag, results in virus replication in the heart but minimal myocarditis. In contrast, Bl.Tg.Eα mice, which are C57BL/6 mice transgenically induced to express IE Ag, develop significant myocarditis upon Coxsackievirus B3 infection. Despite this difference in inflammatory damage, cardiac virus titers are similar between C57BL/6 and Bl.Tg.Eα mice. Removing γδ T cells from either strain by genetic manipulation (γδ knockout(ko)) changes the disease phenotype. C57BL/6 γδ ko mice show increased myocarditis. In contrast, Bl.Tg.Eα γδ ko mice show decreased cardiac inflammation. Flow cytometry revealed a difference in the γδ cell subsets in the two strains, with Vγ1 dominating in C57BL/6 mice, and Vγ4 predominating Bl.Tg.Eα mice. This suggests that these two Vγ-defined subsets might have different functions. To test this possibility, we used mAb injection to deplete each subset. Mice depleted of Vγ1 cells showed enhanced myocarditis, whereas those depleted of Vγ4 cells suppressed myocarditis. Adoptively transfusing enriched Vγ4+ cells to the C57BL/6 and Bl.Tg.Eα γδ ko strains confirmed that the Vγ4 subset promoted myocarditis. Th subset analysis suggests that Vγ1+ cells biased the CD4+ T cells to a dominant Th2 cell response, whereas Vγ4+ cells biased CD4+ T cells toward a dominant Th1 cell response.

“…ϩ T cells, as demonstrated using human synovial T cells activated by Borrelia burgdorferi (92) and in a mouse model of coxsackievirus-induced myocarditis (31). In both these studies CD4…”

Section: Figure 6 Tcr␥␦mentioning

confidence: 99%

Leptospira interrogansActivation of Human Peripheral Blood Mononuclear Cells: Preferential Expansion of TCRγδ+ T Cells vs TCRαβ+ T Cells

Klimpel

Matthias

Vinetz

2003

Innate and adaptive immune responses induced by leptospirosis have not been well characterized. In this study we show that in vitro exposure of naive human PBMC to Leptospira interrogans results in cell proliferation and the production of IFN-γ, IL-12, and TNF-α. Cell proliferation was highest when using high numbers of Leptospira. Optimal cell proliferation occurred at 6–8 days, and the majority of cells contained in these cultures were γ/δ T cells. These cultures showed a 10- to 50-fold expansion of γ/δ T cells compared with the initial cellular input. Additionally, these cultures contained elevated numbers of NK cells. In contrast, exposure of PBMC to low numbers of Leptospira failed to induce γδ T cell or NK cell expansion, but induced significant αβ T cell expansion. Vγ9/Vδ2 were expressed on all γ/δ T cells expanded by exposure of PBMC to Leptospira. Leptospira stimulation of purified TCRγδ+ T cells, obtained from 8-day cultures of Leptorspira-stimulated PBMC, induced high levels of IFN-γ production, but no cell proliferation, suggesting that such stimulation of γδ T cells did not depend on specialized accessory cells or Ag processing. Finally, in patients with acute leptospirosis, there was a significant (4- to 5-fold) increase in the number of peripheral blood TCRγδ+ T cells. These results indicate that Leptospira can activate γδ T cells and αβ T cells and will guide further investigations into the roles of these T cell populations in host defense and/or the pathology of leptospirosis.