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2018 ; 14
(4
): e1006960
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Protection by and maintenance of CD4 effector memory and effector T cell subsets
in persistent malaria infection
#MMPMID29630679
Opata MM
; Ibitokou SA
; Carpio VH
; Marshall KM
; Dillon BE
; Carl JC
; Wilson KD
; Arcari CM
; Stephens R
PLoS Pathog
2018[Apr]; 14
(4
): e1006960
PMID29630679
show ga
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-7R?-) subsets from Early
(TeffEarly, CD62LhiCD27+) to Late (TeffLate, CD62LloCD27-) 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, TeffEarly, 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-7R?hi) subsets, only TemLate
(CD62LloCD27-) reduced peak parasitemia (19%), though the dominant memory subset
is TemEarly, 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 (TemLate, TeffEarly) that may represent correlates
of protection or a target for longer-lived vaccine-induced protection against
malaria blood-stages.
|Animals
[MESH]
|CD4-Positive T-Lymphocytes/*immunology
[MESH]
|Immunologic Memory/*immunology
[MESH]
|Interferon-gamma/biosynthesis
[MESH]
|Malaria/*immunology/pathology/*prevention & control
[MESH]