Immunodominant Dengue Virus-Specific Cd8(+) T Cell Responses Are Associated With A Memory Pd-1(+) Phenotype

Dengue disease is a large public health problem that mainly afflicts tropical and subtropical regions. Understanding of the correlates of protection against dengue virus (DENV) is poor and hinders the development of a successful human vaccine. The present study aims to define DENV-specific CD8(+) T cell responses in general and those of HLA alleles associated with dominant responses in particular. In human blood donors in Nicaragua, we observed a striking dominance of HLA B-restricted responses in general and of the allele B*35: 01 in particular. Comparing these patterns to those in the general population of Sri Lanka, we found a strong correlation between restriction of the HLA allele and the breadth and magnitude of CD8(+) T cell responses, suggesting that HLA genes profoundly influence the nature of responses. The majority of gamma interferon (IFN-gamma) responses were associated with effector memory phenotypes, which were also detected in non-B*35: 01-expressing T cells. However, only the B*35: 01 DENV-specific T cells were associated with marked expression of the programmed death 1 protein (PD-1). These cells did not coexpress other inhibitory receptors and were able to proliferate in response to DENV-specific stimulation. Thus, the expression of particular HLA class I alleles is a defining characteristic influencing the magnitude and breadth of CD8 responses, and a distinct, highly differentiated phenotype is specifically associated with dominant CD8(+) T cells. These results are of relevance for both vaccine design and the identification of robust correlates of protection in natural immunity.