Two sides of the same coin: Protective versus pathogenic CD4 resident memory T cells.

The ability of the adaptive immune system to form memory is key to providing protection against secondary infections. Resident memory T cells (T) are specialized T cell populations that reside within tissue sites where they await reencounter with their cognate antigen. T are distinct from circulating memory cells, including central and effector memory T cells, both functionally and transcriptionally. Since the discovery of T, most research has focused on CD8 T, despite that CD4 T are also abundant in most tissues. In the past few years, more evidence has emerged that CD4 T can contribute both protective and pathogenic roles in disease. A complexity inherent to the CD4 T field is the ability of CD4 T cells to polarize into a multitude of distinct subsets and recognize not only viruses and intracellular bacteria but also extracellular bacteria, fungi, and parasites. In this review, we outline the key features of CD4 T in health and disease, including their contributions to protection against SARS-CoV-2 and potential contributions to immunopathology associated with COVID-19.