Distinct activation phenotype of a highly conserved novel HLA‐B57‐restricted epitope during dengue virus infection

Elizabeth Townsley,Marcia Woda,Alan L Rothman,Robert V Gibbons,Anon Srikiatkhachorn,Siripen Kalayanarooj,Henry A.F Stephens,Anuja Mathew,Stephen J Thomas,Ananda Nisalak,Sharone Green

doi:10.1111/imm.12161

Abstract

Variation in the sequence of T-cell epitopes between dengue virus (DENV) serotypes is believed to alter memory T-cell responses during second heterologous infections. We identified a highly conserved, novel, HLA-B57-restricted epitope on the DENV NS1 protein. We predicted higher frequencies of B57-NS1(26-34) -specific CD8(+) T cells in peripheral blood mononuclear cells from individuals undergoing secondary rather than primary DENV infection. However, high tetramer-positive T-cell frequencies during acute infection were seen in only one of nine subjects with secondary infection. B57-NS1(26-34) -specific and other DENV epitope-specific CD8(+) T cells, as well as total CD8(+) T cells, expressed an activated phenotype (CD69(+) and/or CD38(+)) during acute infection. In contrast, expression of CD71 was largely limited to DENV epitope-specific CD8(+) T cells. In vitro stimulation of cell lines indicated that CD71 expression was differentially sensitive to stimulation by homologous and heterologous variant peptides. CD71 may represent a useful marker of antigen-specific T-cell activation.

Highlights

Dengue virus (DENV), a member of the flavivirus family, consists of four distinct serotypes
Using PBMC samples from Thai children with primary or secondary DENV infection 24, we found that frequencies of B57NS126-34 tetramer-positive T cells were elevated during acute infection
We previously identified HLA-B57-restricted CD8+ T cell lines, which recognized the DENV NS1 or NS2a protein, using convalescent PBMC from a Thai patient with dengue fever (DF) 25

Summary

Introduction

Dengue virus (DENV), a member of the flavivirus family, consists of four distinct serotypes. While host-dependent factors and virus-dependent factors may influence the risk of developing DHF, prospective cohort studies have identified secondary infection with a heterologous DENV serotype as the major risk factor 3. Antibodies and T cells are proposed to contribute to the development of severe dengue disease 7. Other studies have reported higher frequencies of CD8+ T cells expressing CD69, and higher levels of immune activation markers in individuals with DHF as compared to those with DF 11-13. Several studies have reported associations between specific HLA class I alleles and disease severity; these epidemiological links provide additional support for a role of CD8+ T cells in contributing to clinical outcome [14,15,16,17]

Methods

Results

Conclusion