SARS-CoV-2 spike-specific regulatory T cells (Treg) expand and develop memory in vaccine recipients suggesting a role for immune regulation in preventing severe symptoms in COVID-19

Abstract

We enrolled healthy subjects that received 2 to 4 injections of mRNA-based vaccination to prevent COVID-19 months to a year from the last vaccine boost, and we found numerous SARS-CoV-2 spike-specific regulatory T cell (Treg) that developed T cell memory as effector memory T cells (T_EM) and central memory T cells (T_CM). CD4+ CD25^high Treg expressed the chemokine receptor CCR6 in a considerable percentage, suggesting T cell homing to the vascular endothelium, lung and gut epithelial cells and brain. Treg phenotype was different than peripherally-induced Treg (pTreg) that revert from pro-inflammatory T cells under repeated stimulatory conditions, suggesting that SARS-CoV-2 spike-specific Treg differentiated from naïve T cells in tissues where the SARS-CoV-2 spike proteins were synthetized. Twenty two of 22 subjects studied responded to vaccination developing a spike-specific CD4+ T helper (Th)1 response, and 20 of 22 developing a spike-specific CD8+ cytotoxic T cells (CTL) response. However, in vaccine recipients the expansion of spike-specific pro-inflammatory T cells was less significant than the expansion of spike-specific Treg. Effector (T_EM) and central memory (T_CM) Treg were numerous as early as after two vaccine doses, with no significant differences following additional vaccine boosts. In co-culture experiments under stimulatory conditions, Treg regulated naïve T cell differentiation toward a pro-inflammatory phenotype and suppressed interferon (IFN)γ production by SARS-CoV-2-specific CD4 + Th1 cells.

Keywords:

• Regulatory T cells (Treg)
• Vaccine
• SARS-CoV-2
• Immune regulation
• T cell memory

Acknowledgments

The authors thank the subjects that participated to the study.

Disclosure statement

The authors declare no conflict of interest. LJI has filed for patent protection for various aspects of vaccine design and identification of specific epitopes.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.

Additional information

Funding

This study has been funded by a grant from the Resources-Based Center for the Study of the Joint Microenvironment in Rheumatology to A.F.; by a grant from the Academic Senate of the University of California San Diego to A.F.; by the Gordon and Marilyn Macklin Foundation to AF, NIH BARDA division to CC, and by the NIH NIAID, 75N9301900065, to A.S.