Liver damage dampens anti-viral CD8 T cell response by inducing loss of surface T cell receptor expression

Background: Myelin-specific T cells are implicated in multiple sclerosis (MS) and drive experimental autoimmune encephalomyelitis (EAE). EAE is commonly induced with short peptides, whereas in MS, whole myelin proteins are available for immune response. We asked whether immunization with the immunoglobulin-like domain of myelin oligodendrocyte glycoprotein (MOGIgd, residues 1–125) might induce distinct CD4+ T-cell response and/or a stronger CD8+ T-cell response, compared to the 21 amino acid immunodominant MHC II-associating peptide (p35–55). Objectives: Compare both EAE and T-cell responses in C57BL/6 mice immunized with MOGIgd and MOG p35–55. Methods: Cytokine production, and chemokine receptor expression by CD4+ and CD8+ T cells in the mouse central nervous system (CNS), were analyzed by flow cytometry. Results: MOGIgd triggered progression to more severe EAE than MOG p35–55, despite similar time of onset and overall incidence. EAE in MOGIgd-immunized mice was characterized by an increased percentage of CXCR3+ interferon-γ-producing CD4+ T cells in CNS. The CD8+ T-cell response to both immunogens was similar. Conclusions: Increased incidence of severe disease following MOGIgd immunization, accompanied by an increased percentage of CD4+ T cells in the CNS expressing CXCR3 and producing interferon-γ, identifies a pathogenic role for interferon-γ that is not seen when disease is induced with a single Major Histocompatibility Complex (MHC) II-associating epitope.

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CD4+ T cells specific for glycoprotein B from cytomegalovirus exhibit extreme conservation of T-cell receptor usage between different individuals

Blood ◽

10.1182/blood-2007-04-079863 ◽

2008 ◽

Vol 111 (4) ◽

pp. 2053-2061 ◽

Cited By ~ 25

Author(s):

Laura Crompton ◽

Naeem Khan ◽

Rajiv Khanna ◽

Laxman Nayak ◽

Paul A. H. Moss

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Response ◽

Cd4 T Cells ◽

Clonal Selection ◽

Cell Receptor ◽

T Cell Response ◽

Cd4 T Cell ◽

Extreme Conservation

Antigen-specific CD8+ cytotoxic T cells often demonstrate extreme conservation of T-cell receptor (TCR) usage between different individuals, but similar characteristics have not been documented for CD4+ T cells. CD4+ T cells predominantly have a helper immune role, but a cytotoxic CD4+ T-cell subset has been characterized, and we have studied the cytotoxic CD4+ T-cell response to a peptide from human cytomegalovirus glycoprotein B presented through HLA-DRB*0701. We show that this peptide elicits a cytotoxic CD4+ T-cell response that averages 3.6% of the total CD4+ T-cell repertoire of cytomegalovirus-seropositive donors. Moreover, CD4+ cytotoxic T-cell clones isolated from different individuals exhibit extensive conservation of TCR usage, which indicates strong T-cell clonal selection for peptide recognition. Remarkably, this TCR sequence was recently reported in more than 50% of cases of CD4+ T-cell large granular lymphocytosis. Immunodominance of cytotoxic CD4+ T cells thus parallels that of CD8+ subsets and suggests that cytotoxic effector function is critical to the development of T-cell clonal selection, possibly from immune competition secondary to lysis of antigen-presenting cells. In addition, these TCR sequences are highly homologous to those observed in HLA-DR7+ patients with CD4+ T-cell large granular lymphocytosis and implicate cytomegalovirus as a likely antigenic stimulus for this disorder.

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