Open AccessProtection by and maintenance of CD4 effector memory and effector T cell subsets in persistent malaria infection
Author(s) -
Michael M. Opata,
Samad Ibitokou,
Victor H. Carpio,
Karis M. Marshall,
Brian E. Dillon,
Jordan C. Carl,
Kyle D. Wilson,
Christine M. Arcari,
Robin Stephens
Publication year - 2018
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1006960
Subject(s) - parasitemia , effector , biology , plasmodium chabaudi , memory t cell , immunology , t cell , malaria , antigen , microbiology and biotechnology , immune system , virology , plasmodium falciparum
Protection at the peak of Plasmodium chabaudi blood-stage malaria infection is provided by CD4 T cells. We have shown that an increase in Th1 cells also correlates with protection during the persistent phase of malaria; however, it is unclear how these T cells are maintained. Persistent malaria infection promotes protection and generates both effector T cells (Teff), and effector memory T cells (Tem). We have previously defined new CD4 Teff (IL-7Rα - ) subsets from Early (Teff Early , CD62L hi CD27 + ) to Late (Teff Late , CD62L lo CD27 - ) activation states. Here, we tested these effector and memory T cell subsets for their ability to survive and protect in vivo . We found that both polyclonal and P . chabaudi Merozoite Surface Protein-1 (MSP-1)-specific B5 TCR transgenic Tem survive better than Teff. Surprisingly, as Tem are associated with antigen persistence, Tem survive well even after clearance of infection. As previously shown during T cell contraction, Teff Early , which can generate Tem, also survive better than other Teff subsets in uninfected recipients. Two other Tem survival mechanisms identified here are that low-level chronic infection promotes Tem both by driving their proliferation, and by programming production of Tem from Tcm. Protective CD4 T cell phenotypes have not been precisely determined in malaria, or other persistent infections. Therefore, we tested purified memory (Tmem) and Teff subsets in protection from peak pathology and parasitemia in immunocompromised recipient mice. Strikingly, among Tmem (IL-7Rα hi ) subsets, only Tem Late (CD62L lo CD27 - ) reduced peak parasitemia (19%), though the dominant memory subset is Tem Early , which is not protective. In contrast, all Teff subsets reduced peak parasitemia by more than half, and mature Teff can generate Tem, though less. In summary, we have elucidated four mechanisms of Tem maintenance, and identified two long-lived T cell subsets (Tem Late , Teff Early ) that may represent correlates of protection or a target for longer-lived vaccine-induced protection against malaria blood-stages.