Polyfunctional CD4+ T cells are characterized by the expression of activation markers as well as their capacity to produce IFN-γ, IL-2, and TNF-α. These cells have been linked to an excellent response against viral infections and during the development of immunity by vaccination (185, 186). Even though COVID-19 patients have shown an increase in the expression of molecules related to T CD4+ activation, such as CD69, CD38, and CD44, molecules related to their function, such as intracellular IFN-γ, IL-2, and TNF-α, are reduced, especially in individuals with a more severe stage of the disease (9, 170), indicating an impairment of polyfunctional T cells.