title: Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion.
abstract: Naturally acquired immunity to malaria develops slowly, requiring several years of repeated exposure to be effective. The cellular and molecular factors underlying this observation are only partially understood. Recent studies suggest that chronic Plasmodium falciparum exposure may induce functional exhaustion of lymphocytes, potentially impeding optimal control of infection. However, it remains unclear whether the "atypical" memory B cells (MBCs) and "exhausted" CD4 T cells described in humans exposed to endemic malaria are driven by P. falciparum per se or by other factors commonly associated with malaria, such as coinfections and malnutrition. To address this critical question we took advantage of a "natural" experiment near Kilifi, Kenya, and compared profiles of B and T cells of children living in a rural community where P. falciparum transmission is ongoing to the profiles of age-matched children living under similar conditions in a nearby community where P. falciparum transmission ceased 5 y prior to this study. We found that continuous exposure to P. falciparum drives the expansion of atypical MBCs. Persistent P. falciparum exposure was associated with an increased frequency of CD4 T cells expressing phenotypic markers of exhaustion, both programmed cell death-1 (PD-1) alone and PD-1 in combination with lymphocyte-activation gene-3 (LAG-3). This expansion of PD-1-expressing and PD-1/LAG-3-coexpressing CD4 T cells was largely confined to CD45RA(+) CD4 T cells. The percentage of CD45RA(+)CD27(+) CD4 T cells coexpressing PD-1 and LAG-3 was inversely correlated with frequencies of activated and classical MBCs. Taken together, these results suggest that P. falciparum infection per se drives the expansion of atypical MBCs and phenotypically exhausted CD4 T cells, which has been reported in other endemic areas.
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medicine Research Coast, Kilifi, Kenya.
authors.forename: Joseph
authors.initials: J
authors.lastname: Illingworth
authors.forename: Noah S
authors.initials: NS
authors.lastname: Butler
authors.forename: Sophie
authors.initials: S
authors.lastname: Roetynck
authors.forename: Jedida
authors.initials: J
authors.lastname: Mwacharo
authors.forename: Susan K
authors.initials: SK
authors.lastname: Pierce
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
authors.forename: Peter D
authors.initials: PD
authors.lastname: Crompton
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Francis M
authors.initials: FM
authors.lastname: Ndungu
mesh_terms: D000818:Animals; D000852:Anopheles; D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D019353:Endemic Diseases; D004781:Environmental Exposure; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007113:Immunity, Innate; D007156:Immunologic Memory; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D007299:Insect Bites and Stings / Q000453:epidemiology / Q000469:parasitology; D007303:Insect Vectors; D007630:Kenya / Q000453:epidemiology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation / Q000235:genetics; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000276:immunology* / Q000635:transmission; D008297:Male; D010963:Plasmodium falciparum / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis; D012424:Rural Population; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D017493:Leukocyte Common Antigens; D000093322:Lymphocyte Activation Gene 3 Protein