Protection by and maintenance of CD4 effector memory and effector T cell subsets in persistent malaria infection

Autor: Robin Stephens, Victor H. Carpio, Brian E. Dillon, Karis M. Marshall, Jordan C. Carl, Samad Ibitokou, Kyle D. Wilson, Christine M. Arcari, Michael M. Opata
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
CD4-Positive T-Lymphocytes
Quantitative Parasitology
Physiology
Parasitemia
Memory T cells
Plasmodium chabaudi
chemistry.chemical_compound
Mice
White Blood Cells
0302 clinical medicine
T-Lymphocyte Subsets
Animal Cells
Immune Physiology
Medicine and Health Sciences
lcsh:QH301-705.5
Mice
Inbred BALB C
Innate Immune System
biology
Effector
T Cells
Cell Differentiation
3. Good health
medicine.anatomical_structure
Cytokines
Cellular Types
Research Article
lcsh:Immunologic diseases. Allergy
CD4 antigen
T cell
Immune Cells
Immunology
Microbiology
03 medical and health sciences
Interferon-gamma
Antigen
Virology
parasitic diseases
Genetics
medicine
Parasitic Diseases
Animals
Molecular Biology
Blood Cells
Biology and Life Sciences
Cell Biology
Molecular Development
medicine.disease
biology.organism_classification
Tropical Diseases
Malaria
Mice
Inbred C57BL
Chronic infection
030104 developmental biology
chemistry
lcsh:Biology (General)
Immune System
Parasitology
lcsh:RC581-607
Memory T cell
Immunologic Memory
Spleen
030215 immunology
Developmental Biology
Zdroj: PLoS Pathogens, Vol 14, Iss 4, p e1006960 (2018)
PLoS Pathogens
ISSN: 1553-7374
1553-7366
Popis: 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 (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-7Rαhi) 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.
Author summary Malaria causes significant mortality but current vaccine candidates have poor efficacy and duration, as does natural immunity to malaria. T helper cells (CD4+) are essential to protection from malaria, but it is unknown what kinds of T cells would be both protective and long-lasting. Here, we explored the mechanisms of survival used by memory T cells in malaria, and their ability to protect immunodeficient animals from malaria. We identified four mechanisms by which memory T cells are maintained in chronic infection. We also showed that highly activated effector T cells protect better than memory T cells in general, however, effector T cells have a shorter lifespan suggesting a mechanism for short-lived immunity. In total, we identified two protective T cell subsets that are long-lived. Unfortunately, the memory T cell subset that protects, is not the predominant memory T cell population generated by natural infection, suggesting a mechanism for the poor immunity seen in malaria. Our work suggests that vaccines that induce these two T cell subsets may improve on current immunity from malaria infection and disease.
Databáze: OpenAIRE
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