COVID-19, an infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The virus infection can evolve asymptomatically or generate more severe symptoms, influenced by the presence of comorbidities. Lymphopenia in patients affected with COVID-19 according to the severity of symptoms is recurrent, including a decrease in the frequency of NK cells (Natural Killers). However, the profile of CD4+ T, CD8+ T and NK cells in terms of functionality has not yet been well elucidated in acute SARS-CoV-2 infection. The purpose of this study is to evaluate the phenotypic and functional profile of T lymphocytes and NK cells, including memory NK cells, in patients with moderate and severe/critical COVID-19. During the pandemic period, we started analyzing a cohort of 79 patients confirmed with SARS-CoV-2 (31 moderate cases and 48 severe/critical cases) from HC-FMUSP. In this cohort, we observed a death prevalence of 6.5% in moderate cases and 31.3% in severe cases. The most prevalent comorbidities were systemic arterial hypertension and cardiac disorders. Despite lymphopenia, we observed an increase in the expression of activation markers in T lymphocytes (CD28, CD38 and HLA-DR), as well as an increase in the frequency of CD4+ T cells, CD8+ T cells and NK cells that express the immunological checkpoint protein, PD- 1, in patients with severe/critical condition compared to uninfected. In contrast to the percentage decrease in NK cells, there was an increase in the frequency of memory NK, NKG2C+ CD57+ , both in moderate and severe/critical cases of infection. In the skin tissue of patients who died as a result of the disease, we detected an increase in the expression of NKG2C and granzyme in the dermal region. Considering that the expansion of this population is related to exposure to cytomegalovirus (CVM), there was an increase in anti-CMV IgG antibody titers in patients with COVID-19, which normalized in convalescent individuals. As for the cytotoxic profile of peripheral blood mononuclear cells, in the basal condition, an increase in the response of TCD+ 4 and NK cells was observed, however with the stimulation with PMA and Ionomycin little changed. On the other hand, CD8+ T lymphocytes showed a decrease in the cytotoxic response, evidencing a profile of exhaustion in patients with severe COVID-19. In addition, increased constitutive expression of genes associated with the caspase pathway, inflammasome and antiviral factors in purified CD8+ T lymphocytes from patients with severe COVID-19, and reduced expression of TNF-a. The cytotoxic profile, by memory NK cells and cytotoxic CD4+ T cells, can compensate for the dysfunction/exhaustion of CD8+ T cells, however the presence of cells with cytotoxic potential were detected in the dermis of autopsies of COVID-19 patients. These findings may provide a greater understanding of factors associated with the severity of acute COVID-19 infection.