Furthermore, highly speculative hypotheses related to pre-existing memory T cells can be proposed regarding COVID-19 and age. This leads to the speculative hypothesis that differences in CCC geo-distribution might correlate with burden of COVID-19 disease severity. It is well established that the four main CCCs are cyclical in their prevalence, following multiyear cycles, which can differ across geographical locations 8. If the pre-existing T cell immunity is related to CCC exposure, it will become important to better understand the patterns of CCC exposure in space and time. Large studies in which pre-existing immunity is measured and correlated with prospective infection and disease severity could address the possible role of pre-existing T cell memory against SARS-CoV-2. Memory CD4 + and CD8 + T cells might also facilitate direct antiviral immunity in the lungs and nasopharynx early after exposure, in keeping with our understanding of antiviral CD4 + T cells in lungs against the related SARS-CoV 7 and our general understanding of the value of memory CD8 + T cells in protection from viral infections. Memory T follicular helper (T FH) CD4 + T cells could potentially facilitate an increased and more rapid neutralizing antibody response against SARS-CoV-2. It is plausible that people with a high level of pre-existing memory CD4 + T cells that recognize SARS-CoV-2 could mount a faster and stronger immune response upon exposure to SARS-CoV-2 and thereby limit disease severity. Pre-existing T cell immunity to SARS-CoV-2 could be relevant because it could influence COVID-19 disease severity. What are the implications of these observations? The potential for pre-existing crossreactivity against COVID-19 in a fraction of the human population has led to extensive speculation. Taken together, five studies report evidence of pre-existing T cells that recognize SARS-CoV-2 in a significant fraction of people from diverse geographical locations. A study by Meckiff using samples from the UK also detected reactivity in unexposed subjects 5. 4, reported T cell responses to nucleocapsid protein nsp7 or nsp13 in 50% of subjects with no history of SARS, COVID-19, or contact with patients with SARS or COVID-19. Finally, a study of individuals in Singapore, by Le Bert et al. 3 reported positive T cell responses against spike peptides in 34% of SARS-CoV-2 seronegative healthy donors. In a third study, from Germany, Braun et al. CD8 + T cell reactivity was observed in 1 of 10 unexposed donors. 2 detected CD4 + T cell reactivity against SARS-CoV-2 spike peptides in 1 of 10 unexposed subjects and against SARS-CoV-2 non-spike peptides in 2 of 10 unexposed subjects. Similarly, in a study of blood donors in the Netherlands, Weiskopf et al. The SARS-CoV-2 T cell reactivity was mostly associated with CD4 + T cells, with a smaller contribution by CD8 + T cells 1. T cell reactivity was highest against proteins other than the coronavirus spike protein, but T cell reactivity was also detected against spike. 1, reactivity was detected in 50% of donor blood samples obtained in the USA between 20, before SARS-CoV-2 appeared in the human population.
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