Abstract
CD4 T cells orchestrate immunity against blood-stage malaria. However, a major challenge in designing vaccines to the disease is poor understanding of the requirements for the generation of protective memory T cells (Tmem) from responding effector T cells (Teff) in chronic parasite infection. In this study, we use a transgenic mouse model with T cells specific for the merozoite surface protein (MSP)-1 of Plasmodium chabaudi to show that activated T cells generate three distinct Teff subsets with progressive activation phenotypes. The earliest observed Teff subsets (CD127<sup>-</sup>CD62L<sup>hi</sup>CD27<sup>+</sup>) are less divided than CD62L<sup>lo</sup> Teff and express memory genes. Intermediate (CD62L<sup>lo</sup>CD27<sup>+</sup>) effector subsets include the most multicytokine-producing T cells, whereas fully activated (CD62L<sup>lo</sup>CD27<sup>-</sup>) late effector cells have a terminal Teff phenotype (PD-1<sup>+</sup>, Fas<sup>hi</sup>, AnnexinV<sup>+</sup>). We show that although IL-2 promotes expansion, it actually slows terminal effector differentiation. Using adoptive transfer, we show that only early Teff survive the contraction phase and generate the terminal late Teff subsets, whereas in uninfected recipients, they become both central and effector Tmem. Furthermore, we show that progression toward full Teff activation is promoted by increased duration of infection, which in the long-term promotes Tem differentiation. Therefore, we have defined markers of progressive activation of CD4 Teff at the peak of malaria infection, including a subset that survives the contraction phase to make Tmem, and show that Ag and cytokine levels during CD4 T cell expansion influence the proportion of activated cells that can survive contraction and generate memory in malaria infection.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5346-5354 |
| Number of pages | 9 |
| Journal | Journal of Immunology |
| Volume | 194 |
| Issue number | 11 |
| DOIs | |
| State | Published - Jun 1 2015 |
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ASJC Scopus subject areas
- Immunology
Cite this
Early effector cells survive the contraction phase in malaria infection and generate both central and effector memory T cells. / Opata, Michael M.; Carpio, Victor H.; Ibitokou, Akanni Adededji Abdoul; Dillon, Brian E.; Obiero, Joshua M.; Stephens, Robin.
In: Journal of Immunology, Vol. 194, No. 11, 01.06.2015, p. 5346-5354.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Early effector cells survive the contraction phase in malaria infection and generate both central and effector memory T cells
AU - Opata, Michael M.
AU - Carpio, Victor H.
AU - Ibitokou, Akanni Adededji Abdoul
AU - Dillon, Brian E.
AU - Obiero, Joshua M.
AU - Stephens, Robin
PY - 2015/6/1
Y1 - 2015/6/1
N2 - CD4 T cells orchestrate immunity against blood-stage malaria. However, a major challenge in designing vaccines to the disease is poor understanding of the requirements for the generation of protective memory T cells (Tmem) from responding effector T cells (Teff) in chronic parasite infection. In this study, we use a transgenic mouse model with T cells specific for the merozoite surface protein (MSP)-1 of Plasmodium chabaudi to show that activated T cells generate three distinct Teff subsets with progressive activation phenotypes. The earliest observed Teff subsets (CD127-CD62LhiCD27+) are less divided than CD62Llo Teff and express memory genes. Intermediate (CD62LloCD27+) effector subsets include the most multicytokine-producing T cells, whereas fully activated (CD62LloCD27-) late effector cells have a terminal Teff phenotype (PD-1+, Fashi, AnnexinV+). We show that although IL-2 promotes expansion, it actually slows terminal effector differentiation. Using adoptive transfer, we show that only early Teff survive the contraction phase and generate the terminal late Teff subsets, whereas in uninfected recipients, they become both central and effector Tmem. Furthermore, we show that progression toward full Teff activation is promoted by increased duration of infection, which in the long-term promotes Tem differentiation. Therefore, we have defined markers of progressive activation of CD4 Teff at the peak of malaria infection, including a subset that survives the contraction phase to make Tmem, and show that Ag and cytokine levels during CD4 T cell expansion influence the proportion of activated cells that can survive contraction and generate memory in malaria infection.
AB - CD4 T cells orchestrate immunity against blood-stage malaria. However, a major challenge in designing vaccines to the disease is poor understanding of the requirements for the generation of protective memory T cells (Tmem) from responding effector T cells (Teff) in chronic parasite infection. In this study, we use a transgenic mouse model with T cells specific for the merozoite surface protein (MSP)-1 of Plasmodium chabaudi to show that activated T cells generate three distinct Teff subsets with progressive activation phenotypes. The earliest observed Teff subsets (CD127-CD62LhiCD27+) are less divided than CD62Llo Teff and express memory genes. Intermediate (CD62LloCD27+) effector subsets include the most multicytokine-producing T cells, whereas fully activated (CD62LloCD27-) late effector cells have a terminal Teff phenotype (PD-1+, Fashi, AnnexinV+). We show that although IL-2 promotes expansion, it actually slows terminal effector differentiation. Using adoptive transfer, we show that only early Teff survive the contraction phase and generate the terminal late Teff subsets, whereas in uninfected recipients, they become both central and effector Tmem. Furthermore, we show that progression toward full Teff activation is promoted by increased duration of infection, which in the long-term promotes Tem differentiation. Therefore, we have defined markers of progressive activation of CD4 Teff at the peak of malaria infection, including a subset that survives the contraction phase to make Tmem, and show that Ag and cytokine levels during CD4 T cell expansion influence the proportion of activated cells that can survive contraction and generate memory in malaria infection.
UR - http://www.scopus.com/inward/record.url?scp=84929612877&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929612877&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1403216
DO - 10.4049/jimmunol.1403216
M3 - Article
C2 - 25911759
AN - SCOPUS:84929612877
VL - 194
SP - 5346
EP - 5354
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 11
ER -