title: Chronic parasitic infection maintains high frequencies of short-lived Ly6C+CD4+ effector T cells that are required for protection against re-infection.
abstract: In contrast to the ability of long-lived CD8(+) memory T cells to mediate protection against systemic viral infections, the relationship between CD4(+) T cell memory and acquired resistance against infectious pathogens remains poorly defined. This is especially true for T helper 1 (Th1) concomitant immunity, in which protection against reinfection coincides with a persisting primary infection. In these situations, pre-existing effector CD4 T cells generated by ongoing chronic infection, not memory cells, may be essential for protection against reinfection. We present a systematic study of the tissue homing properties, functionality, and life span of subsets of memory and effector CD4 T cells activated in the setting of chronic Leishmania major infection in resistant C57Bl/6 mice. We found that pre-existing, CD44(+)CD62L(-)T-bet(+)Ly6C+ effector (T(EFF)) cells that are short-lived in the absence of infection and are not derived from memory cells reactivated by secondary challenge, mediate concomitant immunity. Upon adoptive transfer and challenge, non-dividing Ly6C(+) T(EFF) cells preferentially homed to the skin, released IFN-γ, and conferred protection as compared to CD44(+)CD62L(-)Ly6C(-) effector memory or CD44(+)CD62L(+)Ly6C(-) central memory cells. During chronic infection, Ly6C(+) T(EFF) cells were maintained at high frequencies via reactivation of T(CM) and the T(EFF) themselves. The lack of effective vaccines for many chronic diseases may be because protection against infectious challenge requires the maintenance of pre-existing T(EFF) cells, and is therefore not amenable to conventional, memory inducing, vaccination strategies.
authors.affiliation: Intracellular Parasite Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Peters
authors.affiliation: Department of Microbiology, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Pagán
authors.affiliation: Intracellular Parasite Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Lawyer
authors.affiliation: Intracellular Parasite Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Hand
authors.affiliation: Intracellular Parasite Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Henrique Roma
authors.affiliation: Intracellular Parasite Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Stamper
authors.affiliation: Intracellular Parasite Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Audrey
authors.initials: A
authors.lastname: Romano
authors.affiliation: Intracellular Parasite Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: David L
authors.initials: DL
authors.lastname: Sacks
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D005260:Female; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D019041:L-Selectin / Q000235:genetics / Q000276:immunology; D018320:Leishmania major / Q000235:genetics / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology*; D051379:Mice
chemical_list: D000950:Antigens, Ly; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C494192:Ly-6C antigen, mouse; D019041:L-Selectin; D007371:Interferon-gamma