Induction of a cytotoxic T cell response by co-injection of a T helper peptide and a cytotoxic T lymphocyte peptide in incomplete Freund's adjuvant (IFA): Further enhancement by pre-injection of IFA alone

ABSTRACT Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an inhibitory T-cell receptor expressed by activated and regulatory T cells. We hypothesized that single-nucleotide polymorphisms (SNPs) in the gene encoding CTLA-4 may affect the vigor of the T-cell response to hepatitis B virus (HBV) infection, thus influencing viral persistence. To test this hypothesis, we genotyped six CTLA4 SNPs, from which all frequent haplotypes can be determined, using a large, matched panel of subjects with known HBV outcomes. Haplotypes with these SNPs were constructed for each subject using PHASE software. The haplotype distribution differed between those with viral persistence and those with clearance. Two haplotypes were associated with clearance of HBV infection, which was most likely due to associations with the SNPs −1722C (odds ratio [OR] = 0.60, P = 0.06) and +49G (OR = 0.73, P = 0.02). The wild-type haplotype, which contains an SNP leading to a decreased T-cell response (+6230A), was associated with viral persistence (OR = 1.32, P = 0.04). These data suggest that CTLA4 influences recovery from HBV infection, which is consistent with the emerging role of T regulatory cells in the pathogenesis of disease.

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Acute Resolving Woodchuck Hepatitis Virus (WHV) Infection Is Associated with a Strong Cytotoxic T-Lymphocyte Response to a Single WHV Core Peptide

Journal of Virology ◽

10.1128/jvi.02711-06 ◽

2007 ◽

Vol 81 (13) ◽

pp. 7156-7163 ◽

Cited By ~ 25

Author(s):

Ina Frank ◽

Claudia Budde ◽

Melanie Fiedler ◽

Uta Dahmen ◽

Sergei Viazov ◽

...

Keyword(s):

T Cell ◽

T Lymphocyte ◽

Cell Response ◽

Cytotoxic T Lymphocyte ◽

Hepatitis Virus ◽

Immunological Response ◽

T Cell Response ◽

Woodchuck Hepatitis Virus ◽

Core Peptide ◽

Ctl Responses

ABSTRACT Woodchucks infected with woodchuck hepatitis virus (WHV) are an excellent model for studying acute, self-limited and chronic hepadnaviral infections. Defects in the immunological response leading to chronicity are still unknown. Specific T-helper cell responses to WHV core and surface antigens (WHcAg and WHsAg, respectively) are associated with acute resolving infection; however, they are undetectable in chronic infection. Up to now, cytotoxic T-lymphocyte (CTL) responses could not be determined in the woodchuck. In the present study, we detected virus-specific CTL responses by a CD107a degranulation assay. The splenocytes of woodchucks in the postacute phase of WHV infection (18 months postinfection) were isolated and stimulated with overlapping peptides covering the whole WHcAg. After 6 days, the cells were restimulated and stained for CD3 and CD107a. One peptide (c96-110) turned out to be accountable for T-cell expansion and CD107a staining. Later, we applied the optimized degranulation assay to study the kinetics of the T-cell response in acute WHV infection. We found a vigorous T-cell response against peptide c96-110 with peripheral blood cells beginning at the peak of viral load (week 5) and lasting up to 15 weeks postinfection. In contrast, there was no T-cell response against peptide c96-110 detectable in chronically WHV-infected animals. Thus, with this newly established flow cytometric degranulation assay, we detected for the first time virus-specific CTLs and determined one immunodominant epitope of WHcAg in the woodchuck.

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Presentation of the H-Y antigen on Langerhans' cell-negative corneal grafts downregulates the cytotoxic T cell response and converts responder strain mice into phenotypic nonresponders.

Journal of Experimental Medicine ◽

10.1084/jem.168.5.1749 ◽

1988 ◽

Vol 168 (5) ◽

pp. 1749-1766 ◽

Cited By ~ 9

Author(s):

J S Peeler ◽

D G Callanan ◽

M W Luckenbach ◽

J Y Niederkorn

Keyword(s):

T Cell ◽

Cell Response ◽

Langerhans Cells ◽

Antigen Expression ◽

T Cell Response ◽

T Helper Cell ◽

Cytotoxic T Cell ◽

T Helper ◽

Active Suppression

We have used the murine cornea is an allograft model to investigate the relative roles of graft-derived IA+ APC (Langerhans' cells) and host-derived APC during the induction of CTL responses to H-Y. The natural exclusion of LC from the immunizing corneal graft led to a specific state of unresponsiveness to H-Y in responder strain mice, while inclusion of LC resulted in responsiveness. Failure to respond to H-Y could not be attributed to the absence of H-Y or IA antigen expression on the surface of LC-deficient grafts but instead, appeared to be due to active suppression of the T helper cell response during in vivo priming. Reprocessing of the H-Y antigen by host APC did not occur after immunization with H-Y presented on H-2-incompatible grafts unless presented initially by graft-derived LC. H-2 as well as some non-H-2 alloantigens were presented to the host without a requirement for donor-derived LC. Thus there appear to be differential requirements for the processing and presentation of alloantigens.

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