AbstractControlled human malaria infection (CHMI) using cryopreserved non-attenuated Plasmodium falciparum sporozoites (PfSPZ) offers a unique opportunity to investigate naturally acquired immunity (NAI). By analyzing blood samples from 5 malaria-naïve European and 20 African adults with lifelong exposure to malaria, before, 5, and 11 days after direct venous inoculation (DVI) with Sanaria^R PfSPZ Challenge, we assessed the immunological patterns associated with control of microscopic and submicroscopic parasitemia. All (5/5) European individuals developed parasitemia as defined by thick blood smear (TBS), but 40% (8/20) of the African individuals controlled their parasitemia, and therefore remained thick blood smear-negative (TBS⁻ Africans). In the TBS⁻ Africans, we observed higher baseline frequencies of CD4⁺ T cells producing interferon-gamma (IFNγ) that significantly decreased 5 days after PfSPZ DVI. The TBS⁻ Africans, which represent individuals with either very strong and rapid blood-stage immunity or with immunity to liver stages, were stratified into subjects with sub-microscopic parasitemia (TBS^-PCR⁺) or those with possibly sterilizing immunity (TBS⁻PCR⁻). Higher frequencies of IFNγ⁺TNF⁺CD8⁺ γδ T cells at baseline, which later decreased within five days after PfSPZ DVI, were associated with those who remained TBS⁻PCR⁻. These findings suggest that naturally acquired immunity is characterized by different cell types that show varying strengths of malaria parasite control. While the high frequencies of antigen responsive IFNγ⁺CD4⁺ T cells in peripheral blood keep the blood-stage parasites to a sub-microscopic level, it is the IFNγ⁺TNF⁺CD8⁺ γδ T cells that are associated with either immunity to the liver-stage, or rapid elimination of blood-stage parasites.