Response of Memory CD8+ T Cells to Severe Acute Respiratory Syndrome (SARS) Coronavirus in Recovered SARS Patients and Healthy Individuals

Abstract

To date, the pathogenesis of severe acute respiratory syndrome (SARS) in humans is still not well understood. SARS coronavirus (SARS-CoV)-specific CTL responses, in particular their magnitude and duration of postinfection immunity, have not been extensively studied. In this study, we found that heat-inactivated SARS-CoV elicited recall CTL responses to newly identified spike protein-derived epitopes (SSp-1, S978, and S1202) in peripheral blood of all HLA-A*0201+ recovered SARS patients over 1 year postinfection. Intriguingly, heat-inactivated SARS-CoV elicited recall-like CTL responses to SSp-1 but not to S978, S1202, or dominant epitopes from several other human viruses in 5 of 36 (13.8%) HLA-A*0201+ healthy donors without any contact history with SARS-CoV. SSp-1-specific CTLs expanded from memory T cells of both recovered SARS patients, and the five exceptional healthy donors shared a differentiated effector CTL phenotype, CD45RA+CCR7−CD62L−, and expressed CCR5 and CD44. However, compared with the high avidity of SSp-1-specific CTLs derived from memory T cells of recovered SARS patients, SSp-1-specific CTLs from the five exceptional healthy donors were of low avidity, as determined by their rapid tetramer dissociation kinetics and reduced cytotoxic reactivity, IFN-γ secretion, and intracellular production of IFN-γ, TNF-α, perforin, and granzyme A. These results indicate that SARS-CoV infection induces strong and long-lasting CTL-mediated immunity in surviving SARS patients, and that cross-reactive memory T cells to SARS-CoV may exist in the T cell repertoire of a small subset of healthy individuals and can be reactivated by SARS-CoV infection.

Immunization with SARS-CoV S DNA vaccine generates memory CD4+ and CD8+ T cell immune responses

“…Furthermore, the function of non-lymphoid effector memory cells has been demonstrated in a study in which Sendai virus specific memory CD4 + T cells persist in the lungs, and transfer of these cells into ␤2-microglobulin-dificient mice confers a significant level of protection against re-infection [24]. Consistent with our observations, several reports demonstrate that natural infection in humans induces memory CD8 + T cells responses [10]. Moreover, immunization of mice with adno-vector encoding codon-optimized SARS-CoV S protein generates two H-2 brestricted epitopes and one H-2 d -restricted epitopes of CD8 + T cells [25].…”

“…These antibodies could inhibit the infection of cells with pseudotyped lentiviral particles bearing SARS-CoV S protein and be used to treat SARS-CoV-infected patients [4][5][6][7]. Recently, several reports including ours have demonstrated that SARS-CoV S specific memory CD8 + T cells were generated and maintained in vivo in the patients with fully recovered from SARS-CoV infection [8][9][10]. These data indicate that the spike protein is a good target for the vaccine to generate immune responses against the SARS-CoV infection.…”

Screening and Identification of Severe Acute Respiratory Syndrome-Associated Coronavirus-Specific CTL Epitopes

“…Studies of the immune response to coronaviruses suggest that both humoral and cellular immunity contribute to protection (61)(62)(63)(64). Recently, existence of memory CTLs against SSp-1, S978, and S1203 epitopes was reported in SARS-recovered patients over 1 year postinfection, and dual roles of CTLs in control of virus replication and immunopathology of acute SARS-CoV infection were suggested (65). It has been proved that DNA vaccine encoding the SARS-CoV S protein may induce effective T cell and neutralizing Ab responses as well as protective immunity in a mouse model (23).…”

The Immunobiology of SARS

“…Two HLA-A2-restricted T cell epitopes in the S protein of SARS-CoV were immunogenic and elicited an overt specific T cell response in patients who survived SARS (130). Stimulation with inactivated SARS-CoV induced a memory CTL response in recovered SARS patients (131) and selective expansion of effector/memory Vγ9Vδ2 T cells. This expansion was associated with higher anti-SARS IgG levels.…”