γδ T Cells Express Activation Markers in the Central Nervous System of Mice with Chronic-relapsing Experimental Autoimmune Encephalomyelitis

Gao, Yanling; Rajan, Alice J.; Raine, Cedric S.; Brosnan, Celia F.

doi:10.1006/jaut.2001.0547

Cited by 25 publications

(19 citation statements)

References 57 publications

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“…Other studies have shown that γδ T cells producing IFN-γ and IL-4 are significantly elevated during EAE [12]. Similar results were reported by Gao and colleagues [37], however in this study it was shown that in both the spleen and CNS of normal mice, there were substantial numbers of CD3 + and γδ T cells secreting both IFN-γ and IL-4. Since the CNS of normal mice is usually devoid of any lymphocyte subset, and particularly of γδ T cells, the meaning of these results is unclear.…”

Section: Introductionsupporting

confidence: 89%

γδ T cells in EAE: Early trafficking events and cytokine requirements

et al. 2009

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We have previously shown that cd T cells traffic to the CNS during EAE with concurrently increased expression of b 2 -integrins and production of IFN-c and TNF-a. To extend these studies, we transferred bioluminescent cd T cells to WT mice and followed their movement through the acute stages of disease. We found that cd T cells rapidly migrated to the site of myelin oligodendrocyte glycoprotein peptide injection and underwent massive expansion. Within 6 days after EAE induction, bioluminescent cd T cells were found in the spinal cord and brain, peaking in number between days 10 and 12 and then rapidly declining by day 15. Reconstitution of cd T cell À/À mice with cd T cells derived from b 2 -integrin-deficient mice (CD11a, -b or -c) demonstrated that cd T-cell trafficking to the CNS during EAE is independent of this family of adhesion molecules. We also examined the role of cd T-cellproduced IFN-c and TNF-a in EAE and found that production of both cytokines by cd T cells was required for full development of EAE. These results indicate that cd T cells are critical for the development of EAE and suggest a therapeutic target in demyelinating disease.Key words: EAE/MS . Neuroimmunology . T cells . Transgenic/knockout mice Introduction gd T cells are one of several T-cell subsets that contribute to the development of EAE, a T-cell-mediated autoimmune disease of the CNS that mimics many aspects of the human disease MS [1][2][3]. Cellular infiltration of the brain and spinal cord by several leukocyte subsets, including gd T cells [4][5][6][7][8], is a characteristic feature of both EAE and MS [1,3]. Although it has been appreciated for some time that gd T cells produce cytokines that contribute to the pro-inflammatory milieu [9][10][11][12][13][14][15] and express adhesion molecules that may be critical for initial priming, trafficking to, and infiltration of the CNS [15][16][17], the significance of their contribution to demyelinating disease remains controversial.gd T cells are considered innate immune T cells by virtue of their limited T-cell receptor repertoire, tissue-specific homing patterns and recognition of non-traditional T-cell antigens [18][19][20][21]. Activation of gd T cells occurs on presentation of phosphoantigens, WC1 molecules or self-antigens by non-classical MHC molecules with cytokines and TLR providing co-stimulation [22][23][24][25][26][27][28][29][30]. Regardless of the priming event(s), trafficking mechanisms employed by gd T cells in demyelinating disease remain ill-defined. Studies have implicated VLA-4 as a participant in gd T-cell adhesion to endothelium, epithelium or fibroblasts, and in transmigration [16,17,31,32], but none have implicated VLA-4 in migration of gd T cells to the CNS. In contrast, gd T cells express all four members of the b 2 -integrin family of adhesion molecules and expression increases through the course of myelin oligodendrocyte glycoprotein (MOG)-induced EAE [15]. Importantly, deletion of three of the four b 2 -integrins (CD11a-c) results in significantly attenuate...

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Section: Introductionsupporting

confidence: 89%

γδ T cells in EAE: Early trafficking events and cytokine requirements

et al. 2009

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“…The lack of a requirement for prior Ag stimulation to promote this response suggested that constitutive expression of activation markers on ␥␦ T cells might be instrumental. It has been shown previously that ␥␦ T cells without stimulation express high levels of activation markers (46,47). The constitutive expression of activation markers by ␥␦ T cells remains to be resolved but may be related to interactions with ubiquitous activation-like receptors.…”

Section: Discussionmentioning

confidence: 97%

γδ T Cells Enhance the Expression of Experimental Autoimmune Encephalomyelitis by Promoting Antigen Presentation and IL-12 Production

Odyniec

Szczepanik

Mycko

et al. 2004

The Journal of Immunology

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Using an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP)-reactive lymph node cells (LNC), we have shown that depletion of γδ T cells from LNC resulted in diminished severity of EAE in recipient mice, both clinically and histopathologically. The reduced potency of γδ T cell-depleted LNC to induce EAE correlated with decreased cell proliferation in response to MBP. The γδ T cell effect upon the threshold of MBP-induced LNC proliferation and EAE transfer was restored by reconstitution of γδ T cells derived from either MBP-immunized or naive mice, indicating that this effect was not Ag specific. The enhancing effect of γδ T cells on MBP-induced proliferation and EAE transfer required direct cell-to-cell contact with LNC. The γδ T cell effect upon the LNC response to MBP did not involve a change in expression of the costimulatory molecules CD28, CD40L, and CTLA-4 on TCRαβ+ cells, and CD40, CD80, and CD86 on CD19+ and CD11b+ cells. However, depletion of γδ T cells resulted in significant reduction in IL-12 production by LNC. That γδ T cells enhanced the MBP response and severity of adoptive EAE by stimulating IL-12 production was supported by experiments showing that reconstitution of the γδ T cell population restored IL-12 production, and that γδ T cell depletion-induced effects were reversed by the addition of IL-12. These results suggest a role for γδ T cells in the early effector phase of the immune response in EAE.

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“…␥␦ T cells have been shown to kill a variety of target cells via Fas/FasL. ␥␦ T cells are known to express FasL at sites of inflammation (6 -8), including the CNS (9). Much of what is known about the functions of Fas/FasL have been learned using lpr and gld mice, which carry spontaneous mutations in the Fas and FasL genes, respectively (10).…”

Section: ␥␦ T Cells Regulate the Extent And Duration Of Inflammation mentioning

confidence: 99%

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

Ponomarev

Dittel

2005

The Journal of Immunology

112

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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.

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γδ T Cells Express Activation Markers in the Central Nervous System of Mice with Chronic-relapsing Experimental Autoimmune Encephalomyelitis

Cited by 25 publications

References 57 publications

γδ T cells in EAE: Early trafficking events and cytokine requirements

γδ T cells in EAE: Early trafficking events and cytokine requirements

γδ T Cells Enhance the Expression of Experimental Autoimmune Encephalomyelitis by Promoting Antigen Presentation and IL-12 Production

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

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