UC Berkeley

P. falciparum (Pf) causes millions of cases of clinical malaria and hundreds of thousands of deaths each year, primarily in children under the age of five in sub-Saharan Africa. With increasing drug resistance, the need for an effective malaria vaccine is evident. In order to design an effective malaria vaccine, the immunological correlates of protection from malaria must be better understood. This is particularly important to understand in endemic populations given that many malaria vaccine candidates that were promising in naïve individuals were significantly less effective in endemic populations. Here, we examine the role that the innate and innate-like lymphocytes, NK cells and Vγ9V?2 T cells (V?2s), respectively, play in the immune response to malaria and how they are altered by chronic Pf exposure. We found that NK cells, like V?2s, are altered by chronic Pf exposure and shift towards a higher proportion of CD56negCD16+ NK cells but are able to recover after the chronic exposure is stopped. These CD56negCD16+ NKs are less likely to respond to cytokine stimulation but are effective at antibody dependent cellular cytotoxicity (ADCC). We next examined the role that inhibitory receptors on these innate(-like) lymphocytes might play in dampening the malarial immune response. First, we analyzed individuals’ killer cell immunoglobulin-like receptors (KIRs) and their HLA ligand repertoires and found that two KIR-HLA ligand pairs were associated with an increase in parasite prevalence. Then, we studied the expression of KIRs in addition to two other inhibitory receptors with MHC-I ligands, LILRB1 and NKG2a, on V?2s. We observed that chronic Pf exposure was associated with an increase in KIRs and LILRB1 on V?2s and that V?2s with these inhibitory receptors were less likely to respond to TCR stimulation than their inhibitory receptor negative counterparts. Altogether, these data indicate that chronic Pf exposure leads to an immune repertoire that is less responsive to more generalized, soluble stimuli in part due to inhibitory receptors and instead takes advantage of the specificity of antibodies developed during chronic exposure to have a more narrow response. However, the importance of robust V?2 and NK cell responses during early infections is highlighted by the association of two inhibitory KIR-HLA ligand pairs with an increase in parasite prevalence suggesting impaired parasite clearance by the immune system. These findings have the potential to help guide future vaccine design targeted at Pf endemic populations by directing the immune response to cells that have maintained their Pf responsiveness or by strongly stimulating cells that have become less responsive to Pf stimuli.