Massive Load of Functional Effector CD4+ and CD8+ T Cells against Cytomegalovirus in Very Old Subjects

TAP translocates virus-derived peptides from the cytosol into the endoplasmic reticulum, where the peptides are loaded onto MHC class I molecules. This process is crucial for the detection of virus-infected cells by CTL that recognize the MHC class I-peptide complexes at the cell surface. The varicellovirus bovine herpesvirus 1 encodes a protein, UL49.5, that acts as a potent inhibitor of TAP. UL49.5 acts in two ways, as follows: 1) by blocking conformational changes of TAP required for the translocation of peptides into the endoplasmic reticulum, and 2) by targeting TAP1 and TAP2 for proteasomal degradation. At present, it is unknown whether UL49.5 interacts with TAP1, TAP2, or both. The contribution of other members of the peptide-loading complex has not been established. Using TAP-deficient cells reconstituted with wild-type and recombinant forms of TAP1 and TAP2, TAP was defined as the prime target of UL49.5 within the peptide-loading complex. The presence of TAP1 and TAP2 was required for efficient interaction with UL49.5. Using deletion mutants of TAP1 and TAP2, the 6+6 transmembrane core complex of TAP was shown to be sufficient for UL49.5 to interact with TAP and block its function. However, UL49.5-induced inhibition of peptide transport was most efficient in cells expressing full-length TAP1 and TAP2. Inhibition of TAP by UL49.5 appeared to be independent of the presence of other peptide-loading complex components, including tapasin. These results demonstrate that UL49.5 acts directly on the 6+6 transmembrane TAP core complex of TAP by blocking essential conformational transitions required for peptide transport.

Section: Ajor Histocompatibility Complex Class I-mediated Peptide Pmentioning

confidence: 93%

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

Verweij

Koppers-Lalić

Loch

et al. 2008

“…1). The responses specific for peptides m18 872-886 , M25 409 -423 , m139 560 -574 , m141 [181][182][183][184][185][186][187][188][189][190][191][192][193][194][195] , and m142 24 -38 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] . The sum of these individual responses represented ϳ1.5% of the total splenic CD4 T cells following MCMV infection.…”

Section: Identification Of Mcmv-specific I-a B -Restricted Cd4 T Cellmentioning

confidence: 99%

“…Approximately 4 -5% of the entire CD4 and CD8 T cell compartment is specific for HCMV in seropositive humans (9) and can increase dramatically in the elderly (10,11). Specific subpopulations of MCMV-specific CD8 T cells also increase over time (e.g., "memory inflation") (12)(13)(14)(15).…”

mentioning

confidence: 99%

Cutting Edge: Murine Cytomegalovirus Induces a Polyfunctional CD4 T Cell Response

Arens¹,

Wang

Sidney

et al. 2008

132

CD4 T lymphocytes regulate the adaptive immune response to most viruses, both by providing help to CD8 T cells and B cells as well as through direct antiviral activity. Currently, no mouse cytomegalovirus (MCMV)-specific CD4 T cell responses are known. In this study, we identify and characterize 15 I-Ab-restricted CD4 T cell responses specific for MCMV epitopes. CD4 T cells accumulate to high levels in the spleen and lungs during acute infection and produce multiple cytokines (IFN-γ, TNF, IL-2, IL-10, and IL-17). Interestingly, IL-17 and IFN-γ production within epitope-specific cells was found to be mutually exclusive. CD4 T cells recognizing a peptide derived from m09 were only detectable at later times of infection and displayed a unique cytokine production profile. In total, this study reveals that the MCMV-specific CD4 T cell response is complex and functionally diverse, highlighting its important role in controlling this persistent pathogen.

“…In CMV-seropositive donors, one tenth, on average, of the total memory T cell population responds to CMV Ags in vitro (15). The CMV-specific T cell pool becomes even larger in old age (16,17) and may then become harmful, because CMV seropositivity is associated with a reduced response to other viruses (18,19), as well as increased mortality (20). Thus, this immuno-obsession with CMV may be at the expense of other useful immune responses.…”

mentioning

confidence: 99%

Functional Killer Ig-Like Receptors on Human Memory CD4+ T Cells Specific for Cytomegalovirus

Bergen

Kooy-Winkelaar

Dongen

et al. 2009

Although very few CD4+ T cells express killer Ig receptors (KIR), a large proportion of CD4+ T cells with a late memory phenotype, characterized by the absence of CD28, does express KIR. Here, we show that KIR expression on CD4+ T cells is also associated with memory T cell function, by showing that the frequency of CMV-specific cells is higher in CD4+KIR+ than CD4+KIR− T cells. In addition, engagement of an inhibitory KIR inhibited the CMV-specific proliferation of these CD4+KIR+ memory T cells, but had no detectable effect on cytokine production. Our data reveal that, in marked contrast with CD8+ T cells, the activity of a subset of CMV-specific CD4+ T cells is modulated by HLA class I-specific KIR. Thus, the CMV-induced down-regulation of HLA class I may in fact enhance memory CMV-specific CD4+ T cell responses restricted by HLA class II.