title: Memory CD4+ T-cell-mediated protection depends on secondary effectors that are distinct from and superior to primary effectors.
abstract: Whether differences between naive cell-derived primary (1°) and memory cell-derived secondary (2°) CD4(+) T-cell effectors contribute to protective recall responses is unclear. Here, we compare these effectors directly after influenza A virus infection. Both develop with similar kinetics, but 2° effectors accumulate in greater number in the infected lung and are the critical component of memory CD4(+) T-cell-mediated protection against influenza A virus, independent of earlier-acting memory-cell helper functions. Phenotypic, functional, and transcriptome analyses indicate that 2° effectors share organ-specific expression patterns with 1° effectors but are more multifunctional, with more multicytokine (IFN-γ(+)/IL-2(+)/TNF(+))-producing cells and contain follicular helper T-cell populations not only in the spleen and draining lymph nodes but also in the lung. In addition, they express more CD127 and NKG2A but less ICOS and Lag-3 than 1° effectors and express higher levels of several genes associated with survival and migration. Targeting two differentially expressed molecules, NKG2A and Lag-3, reveals differential regulation of 1° and 2° effector functions during pathogen challenge.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA. tara.strutt@umassmed.edu
authors.forename: Tara M
authors.initials: TM
authors.lastname: Strutt
authors.forename: K Kai
authors.initials: KK
authors.lastname: McKinstry
authors.forename: Yi
authors.initials: Y
authors.lastname: Kuang
authors.forename: Linda M
authors.initials: LM
authors.lastname: Bradley
authors.forename: Susan L
authors.initials: SL
authors.lastname: Swain
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002645:Chickens; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D007156:Immunologic Memory / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000096:biosynthesis; D009980:Influenza A virus / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis; D007700:Kinetics; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000096:biosynthesis; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D013154:Spleen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2; D053699:Interleukin-7 Receptor alpha Subunit; D055654:NK Cell Lectin-Like Receptor Subfamily C; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000093322:Lymphocyte Activation Gene 3 Protein