Severity-associated changes in ICOS, CD27, CD127 and CLA expression and expansion of virus-specific T Cells in acute dengue
Heshan Kuruppu, Malithi De Silva, Chathumini Dissanayake, Radanee Rathnapriya, Ananda Wijewickrama, Damayanthi Idampitiya, Lakshmanane Premkumar, Chandima Jeewandara, Graham Ogg, Gathsaurie Neelika MalavigeAbstract
Background
Currently the role of dengue virus (DENV) specific T cell responses in disease pathogenesis and protection are not well understood, including potential differences in those who have obesity. We sought to investigate the functionality and phenotype of T cells in patients with acute dengue fever (DF) or dengue haemorrhagic fever (DHF).
Methods
T cell function was assessed in paired samples (first sample on ≤4 days and second 5-6 since onset of illness) in patients with DF (n=50) and DHF (n=12), using 109 peptides representing CD8+ epitopes and 90 peptides targeting CD4+ T cell epitopes. Phenotypic analysis was in DF (n=21) and DHF patients (n=21), recruited between days 6–8 since onset of illness, by multicolor flow cytometry.
Results
The frequency of ex vivo IFNγ ELISpot responses to both the CD4+ and CD8+ peptides pools significantly increased from the first (F) to second time (S) point in patients with DF (p<0.0001) but not with DHF. The frequency of ex vivo IFNγ ELISpot responses to CD4+ (p=0.001) and CD8+ peptides pools (p=0.0002) also significantly increased from the F to S in lean patients but not in obese patients. Cutaneous lymphocyte associated antigen (CLA) expression was significantly higher in the CD8+ T cell subset in patients with DF and DHF compared to HC and these differences were most significant in CD8+CD45RA- T cells. CD8+CD45RA-CLA+ T cells consisted of >50% of the T cells in 9/21 patients with DHF, with 92.7% expressing CD38. CLA expression was highest in the CD8+CD45RA- of obese individuals, which was significantly higher compared to lean individuals (p=0.01). CD27 and CD127 were both significantly downregulated in patients with DHF compared to DF, with ICOS expression being significantly higher in CD8+ T cells in DHF.
Discussion
Patients with DHF and obese individuals had impaired T cell functionality compared to patients with DF and lean individuals, with an expansion of activated, skin-homing CD8+ T cells exhibiting downregulation of CD27 and CD127. Our data suggest a contributory role of dysfunctional skin-homing T cells in disease pathogenesis, meriting further investigation.