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_RM) are specialized T cell populations that reside within tissue sites where they await reencounter with their cognate antigen. T_RM are distinct from circulating memory cells, including central and effector memory T cells, both functionally and transcriptionally. Since the discovery of T_RM, most research has focused on CD8⁺ T_RM, despite that CD4⁺ T_RM are also abundant in most tissues. In the past few years, more evidence has emerged that CD4⁺ T_RM can contribute both protective and pathogenic roles in disease. A complexity inherent to the CD4⁺ T_RM 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_RM in health and disease, including their contributions to protection against SARS-CoV-2 and potential contributions to immunopathology associated with COVID-19.