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2.
Cell Rep ; 42(10): 113182, 2023 10 31.
Article in English | MEDLINE | ID: mdl-37776519

ABSTRACT

Cytotoxic CD4 T cell effectors (ThCTLs) kill virus-infected major histocompatibility complex (MHC) class II+ cells, contributing to viral clearance. We identify key factors by which influenza A virus infection drives non-cytotoxic CD4 effectors to differentiate into lung tissue-resident ThCTL effectors. We find that CD4 effectors must again recognize cognate antigen on antigen-presenting cells (APCs) within the lungs. Both dendritic cells and B cells are sufficient as APCs, but CD28 co-stimulation is not needed. Optimal generation of ThCTLs requires signals induced by the ongoing infection independent of antigen presentation. Infection-elicited type I interferon (IFN) induces interleukin-15 (IL-15), which, in turn, supports CD4 effector differentiation into ThCTLs. We suggest that these multiple spatial, temporal, and cellular requirements prevent excessive lung ThCTL responses when virus is already cleared but ensure their development when infection persists. This supports a model where continuing infection drives the development of multiple, more differentiated subsets of CD4 effectors by distinct pathways.


Subject(s)
Antineoplastic Agents , Interferon Type I , Interleukin-15 , CD4-Positive T-Lymphocytes , Histocompatibility Antigens Class II/metabolism , T-Lymphocytes, Cytotoxic , Antigens
3.
J Immunol ; 210(12): 1950-1961, 2023 06 15.
Article in English | MEDLINE | ID: mdl-37093656

ABSTRACT

Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity for peptide at this "effector checkpoint" dictates the extent of memory and degree of protection against rechallenge. We made an influenza A virus nucleoprotein (NP)-specific TCR transgenic mouse strain, FluNP, and generated NP-peptide variants that are presented by MHC class II to bind to the FluNP TCR over a broad range of avidity. To evaluate the impact of avidity in vivo, we primed naive donor FluNP in influenza A virus-infected host mice, purified donor effectors at the checkpoint, and cotransferred them with the range of peptides pulsed on activated APCs into second uninfected hosts. Higher-avidity peptides yielded higher numbers of FluNP memory cells in spleen and most dramatically in lung and draining lymph nodes and induced better protection against lethal influenza infection. Avidity determined memory cell number, not cytokine profile, and already impacted donor cell number within several days of transfer. We previously found that autocrine IL-2 production at the checkpoint prevents default effector apoptosis and supports memory formation. Here, we find that peptide avidity determines the level of IL-2 produced by these effectors and that IL-2Rα expression by the APCs enhances memory formation, suggesting that transpresentation of IL-2 by APCs further amplifies IL-2 availability. Secondary memory generation was also avidity dependent. We propose that this regulatory pathway selects CD4 effectors of highest affinity to progress to memory.


Subject(s)
CD4-Positive T-Lymphocytes , Interleukin-2 , Mice , Animals , CD4-Positive T-Lymphocytes/metabolism , Interleukin-2/metabolism , Peptides/metabolism , Mice, Transgenic , Receptors, Antigen, T-Cell/metabolism , Immunologic Memory , Mice, Inbred C57BL
4.
Aging Cell ; 21(10): e13705, 2022 10.
Article in English | MEDLINE | ID: mdl-36056604

ABSTRACT

Age-associated B cells (ABC) accumulate with age and are associated with autoimmunity and chronic infection. However, their contributions to acute infection in the aged and their developmental pathways are unclear. We find that the response against influenza A virus infection in aged mice is dominated by a Fas+ GL7- effector B cell population we call infection-induced ABC (iABC). Most iABC express IgM and include antibody-secreting cells in the spleen, lung, and bone marrow. We find that in response to influenza, IgD+ CD21- CD23- ABC are the precursors of iABC and become memory B cells. These IgD+ ABC develop in germ-free mice, so are independent of foreign antigen recognition. The response of ABC to influenza infection, resulting in iABC, is T cell independent and requires both extrinsic TLR7 and TLR9 signals. In response to influenza infection, IgD+ ABC can induce a faster recovery of weight and higher total anti-influenza IgG and IgM titers that can neutralize virus. Immunization with whole inactivated virus also generates iABC in aged mice. Thus, in unimmunized aged mice, whose other B and T cell responses have waned, IgD+ ABC are likely the naive B cells with the potential to become Ab-secreting cells and to provide protection from infection in the aged.


Subject(s)
Influenza Vaccines , Influenza, Human , Animals , Humans , Mice , Antibodies, Viral , Immunoglobulin D , Immunoglobulin G , Immunoglobulin M , Toll-Like Receptor 7 , Toll-Like Receptor 9 , Vaccines, Inactivated , B-Lymphocytes , T-Lymphocytes
5.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Article in English | MEDLINE | ID: mdl-35177472

ABSTRACT

While influenza infection induces robust, long-lasting, antibody responses and protection, including the T follicular helper cells (TFH) required to drive B cell germinal center (GC) responses, most influenza vaccines do not. We investigated the mechanisms that drive strong TFH responses during infection. Infection induces viral replication and antigen (Ag) presentation lasting through the CD4 effector phase, but Ag and pathogen recognition receptor signals are short-lived after vaccination. We analyzed the need for both infection and Ag presentation at the effector phase, using an in vivo sequential transfer model to time their availability. Differentiation of CD4 effectors into TFH and GC-TFH required that they recognize Ag locally in the site of TFH development, at the effector phase, but did not depend on specific Ag-presenting cells (APCs). In addition, concurrent signals from infection were necessary even when sufficient Ag was presented. Providing these signals with a second dose of live attenuated influenza vaccine at the effector phase drove TFH and GC-TFH development equivalent to live infection. The results suggest that vaccine approaches can induce strong TFH development that supports GC responses akin to infection, if they supply these effector phase signals at the right time and site. We suggest that these requirements create a checkpoint that ensures TFH only develop fully when infection is still ongoing, thereby avoiding unnecessary, potentially autoimmune, responses.


Subject(s)
Influenza Vaccines/immunology , Influenza, Human/immunology , T Follicular Helper Cells/immunology , Animals , Antibodies, Viral/immunology , Antibody Formation/immunology , Antigens , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Female , Germinal Center/immunology , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , T Follicular Helper Cells/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Vaccines, Attenuated/immunology
6.
Virology ; 539: 26-37, 2020 01 02.
Article in English | MEDLINE | ID: mdl-31670188

ABSTRACT

In addition to direct anti-viral activity, NK cells regulate viral pathogenesis by virtue of their cytolytic attack on activated CD4 and CD8 T cells. To gain insight into which differentiated T cell subsets are preferred NK targets, transgenic T cells were differentiated in vitro into Th0, Th1, Th2, Th17, Treg, Tc1, and Tc2 effector cells and then tested for lysis by enriched populations of lymphocytic choriomeningitis virus (LCMV)-induced activated NK cells. There was a distinct hierarchy of cytotoxicity in vitro and in vivo, with Treg, Th17, and Th2 cells being more sensitive and Th0 and Th1 cells more resistant. Some distinctions between in vitro vs in vivo generated T cells were explainable by type 1 interferon induction of class 1 histocompatibility antigens on the effector T cell subsets. NK receptor (NKR)-deficient mice and anti-NKR antibody studies identified no one essential NKR for killing, though there could be redundancies.


Subject(s)
Cytotoxicity, Immunologic , Killer Cells, Natural/immunology , Killer Cells, Natural/virology , T-Lymphocyte Subsets/immunology , Animals , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cytotoxicity, Immunologic/drug effects , Interferons/genetics , Interferons/pharmacology , Lymphocytic Choriomeningitis/immunology , Lymphocytic choriomeningitis virus/immunology , Lymphocytic choriomeningitis virus/pathogenicity , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Receptors, Natural Killer Cell/antagonists & inhibitors , Receptors, Natural Killer Cell/genetics , T-Lymphocyte Subsets/drug effects
7.
J Immunol ; 198(3): 1142-1155, 2017 02 01.
Article in English | MEDLINE | ID: mdl-28031335

ABSTRACT

CD4 T cells can differentiate into multiple effector subsets, including ThCTL that mediate MHC class II-restricted cytotoxicity. Although CD4 T cell-mediated cytotoxicity has been reported in multiple viral infections, their characteristics and the factors regulating their generation are unclear, in part due to a lack of a signature marker. We show in this article that, in mice, NKG2C/E identifies the ThCTL that develop in the lung during influenza A virus infection. ThCTL express the NKG2X/CD94 complex, in particular the NKG2C/E isoforms. NKG2C/E+ ThCTL are part of the lung CD4 effector population, and they mediate influenza A virus-specific cytotoxic activity. The phenotype of NKG2C/E+ ThCTL indicates they are highly activated effectors expressing high levels of binding to P-selectin, T-bet, and Blimp-1, and that more of them secrete IFN-γ and readily degranulate than non-ThCTL. ThCTL also express more cytotoxicity-associated genes including perforin and granzymes, and fewer genes associated with recirculation and memory. They are found only at the site of infection and not in other peripheral sites. These data suggest ThCTL are marked by the expression of NKG2C/E and represent a unique CD4 effector population specialized for cytotoxicity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cytotoxicity, Immunologic , Influenza A virus , NK Cell Lectin-Like Receptor Subfamily C/analysis , Orthomyxoviridae Infections/immunology , Animals , Biomarkers/analysis , CD4-Positive T-Lymphocytes/chemistry , CD4-Positive T-Lymphocytes/classification , Interferon-gamma/biosynthesis , Lung/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Positive Regulatory Domain I-Binding Factor 1 , Transcription Factors/analysis
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