Understanding the T cell immune response in SARS coronavirus infection

Janice Oh, Hsueh-Ling; Ken-En Gan, Samuel; Bertoletti, Antonio; Tan, Yee-Joo

To date, there is only one study that investigated T cell response against whole SARS-CoV in humans. 34 In this study, PBMCs from 1-year post-infected patients showed T cell response to eight (replicase, S, N, E, M, 3a, 3b, and 9b) out of the fourteen SARS-CoV proteins when tested using overlapping peptides spanning the entire SARS-CoV genome. Of the 70% of T cell responses elicited against the structural proteins, the S protein induced the most dominant responses (41%). In fact, the three most commonly recognized T cell epitope were that of one found in 3a, and the other two in the S protein (S435-451 and S633-650). The latter were not reported in the other studies. Although both CD4 1 and CD8 1 T cell responses were observed in the study, the frequency and magnitude of the CD8 1 T cell responses were greater than the CD4 1 T cell responses. However, the CD4 1 and CD8 1 T cells were found to have similar central memory phenotypes (CD27 1 and CD45RO 1 ) . A separate study by Peng et al. showed that the N-specific CD4 1 T cells had central memory (CD45RA 2 CCR7 1 CD62L 2 ), whereas most of the CD8 1 T cells had effector memory (CD45RA 1 CCR7 2 CD62L 2 ) phenotype. 28 Similar observations were made with the M-specific CD4 1 and CD8 1 T cells, 41 whilst the S-specific CD8 1 T cells were reported to have effector memory (CD45RA 1 CCR7 2 CD62L 2 ) phenotype. 21 Using peptides in the four SARS-CoV structural proteins, an analysis of the memory T cell response in recovered SARS patients four years post-infection revealed that both CD4 1 and CD8 1 T cells produced IFNc. 43 In support of Li et al.'s study, 34 Fan et al. also found that CD4 1 memory T cells produce IL-2, TNFa and IFNc, with the exception of one patient. 43 It was also observed that S peptides induced the highest percentages of IFNc producing cells. Interestingly, the frequency of these polyfunctional CD4 1 T cells (T cells producing multiple cytokines) was higher in the individuals with severe SARS infection than in moderately severe patients. 34 On the other hand, this difference between moderate severe and severe patients was Nonetheless, a proportion of the CD8 1 T cells were found to produce TNFa and degranulate (with the detection of CD107a). Since polyfunctional T cells were associated with better control of human immunodeficiency virus (HIV) infection and vaccination efficacy, 44, 45 we further characterized the cytokine profile of the SARSspecific T cells in our recent study. 33 A summary of our findings is shown in Figure 1 . We have observed that the majority of CD4 1 T cells produced IFNc, IL-2, and TNFa, with a small percentage of the cells also simultaneously producing inflammatory cytokines such as macrophage inflammatory protein (MIP) 1a, MIP 1b and granulocyte-macrophage colony-stimulating factor (GM-CSF). Of these, the majority of the CD8 1 T cells produced IFNc, TNFa, MIP 1a or MIP 1b alone or in combination. Only a small percentage produced IFNc, IL-2, and TNFa. Moving forward, we cloned the a and b T cell receptor (TCR) chains of one immunodominant CTL epitope in the N protein (amino acid 216 to 225) from the SARS-CoV specific CD8 1 T cells and used them to redirect the specificity of lymphocytes of healthy subjects lacking SARS-CoV specific memory T cells. These TCR-redirected T cells were found to possess a cytokine production profile similar to SARS-CoV specific memory CD8 1 T cells in recovered SARS patients (as mentioned above). Thus we proposed that thes