Early effector cells survive the contraction phase in malaria infection and generate both central and effector memory T cells.
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(-)CD62L(hi)CD27(+)) are less divided than CD62L(lo) Teff and express memory genes. Intermediate (CD62L(lo)CD27(+)) effector subsets include the most multicytokine-producing T cells, whereas fully activated (CD62L(lo)CD27(-)) late effector cells have a terminal Teff phenotype (PD-1(+), Fas(hi), 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.
Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; and.
Michael M
MM
Opata
Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; and Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
Victor H
VH
Carpio
Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; and.
Samad A
SA
Ibitokou
Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; and.
Brian E
BE
Dillon
Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; and.
Joshua M
JM
Obiero
Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; and Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555 rostephe@utmb.edu.
Robin
R
Stephens
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000276:immunology; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008288:Malaria / Q000276:immunology*; D020066:Merozoite Surface Protein 1 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016788:Plasmodium chabaudi / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
D016207:Cytokines; D007376:Interleukin-2; D053699:Interleukin-7 Receptor alpha Subunit; D020066:Merozoite Surface Protein 1; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019041:L-Selectin; D007371:Interferon-gamma