The overlooked role of T cells in the antiviral response


Recent reports on the immune response to SARS-CoV-2 infection have largely focussed on B cells, with particular emphasis placed on antibody testing. An antibody response can typically be detected within 15-30 days of the onset of COVID-19 symptoms but concerns have been raised about the persistence of antibodies. A U.K. study reported a rapid decline in antibody titres, with the level of neutralizing antibodies in some patients approaching baseline within two months of disease onset (Seow et al. medRxiv preprint; free download at This has raised concerns about whether a COVID-19 vaccine would confer long-lasting immunity.

However, the emphasis on B cells overlooks the importance of CD4+ and CD8+ T cells in the early immune response to CoV-2. A robust T cell response appears to be important in limiting disease severity in other coronavirus infections. Indeed, a reduction in CD8+ and CD4+ T cells has been  shown to be associated with worse clinical outcomes in patients with SARS (Li et al. J Infect Dis 2004;189:648-651) (see MS and Coronavirus have a long history, NeuroSens, April 9, 2020).

Two new studies support the importance of the T cell response to SARS-CoV-2 infection. A U.S study examined convalescent blood samples from 20 patients who had recovered from COVID-19 (Grifoni et al. Cell 2020;181:1489-1501). CD4+ and CD8+ T cell responses were detected in 100% and 70%, respectively, of recovered COVID-19 patients. About 50% of the CD4+ response was directed against the CoV-2 Spike protein. The CD4+ and CD8+ T cell response to Spike (but not non-Spike) antigen was correlated with IgG titres. However, a concern is that 50% of the CD4+ response was directed at non-Spike antigens (e.g. nucleocapsid), raising the question of whether a vaccine employing a broader range of viral epitopes might elicit a more robust host response. Most COVID vaccines currently in development have focussed on S protein antigens (see Vaccines in development for COVID-19, NeuroSens, May 5, 2020). One vaccine candidate, BNT162, does target multiple antigens and was recently reported to elicit a robust CD4+/CD8+ response (Sahin et al. medRxiv preprint. Free full text at

Interestingly, Grifoni and colleagues also reported that 50% of individuals with no exposure to SARS-CoV-2 showed non-Spike-specific CD4+ T cell reactivity. This suggests some degree of cross-reactivity, raising the possibility that individuals who have been exposed to other coronaviruses (e.g. the common cold viruses HCoV-OC43 and -229E) may have some immunity to CoV-2 and will have a less severe clinical course.

A second study has reported similar findings. A group in Singapore reported that blood samples collected from SARS patients 17 years ago still harboured T cells that were reactive against SARS; this T cell population rapidly proliferated in response to CoV-2 structural proteins (e.g. nucleocapsid protein, NP). Remarkably, a SARS-CoV-2-specific T cell response was also seen in 19 of 37 individuals who had never been exposed to CoV-2 or SARS. The memory T cell response differed depending on prior virus exposure: SARS and COVID-19 patients reacted primarily to NP peptides whereas unexposed individuals had a mixed response to structural (e.g. NP) and non-structural (e.g. NSP7/13) peptides.

These findings suggest that some peptide sequences are conserved in different coronaviruses, raising the possibility that prior coronavirus exposure may confer some degree of immunity to CoV-2. It may also help to explain the differing clinical severity in patients who contract COVID-19. It remains to be seen if the emerging importance of T cells in combatting CoV-2 infection will lead to a reappraisal of the relative merits of different disease-modifying therapies in the treatment of multiple sclerosis during the COVID-19 pandemic.

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