Generation and Persistence of CD4 Memory Subsets Recently we found that flu-specific CD4 T cell effectors provide protection against lethal challenge by virtue of both direct cytolytic activity (ThCTL) and help for Ab, suggesting additional functional heterogeneity among CD4 subsets that may contribute to CD4 memory heterogeneity and help us uncover new mechanisms of vaccine-induced protection. We have recent evidence that IL-17 producing CD4 also play a role in combating influenza. Our goal here is to evaluate the hypothesis that ThCTL cells represent a distinct functionally specialized subset that with Th1 and Th17 participate in an effective immune response. We will compare ThCTL to Th17 and Th1 subsets at the effector stage to further define their respective functions and determine how they provide protection in the lung against influenza. We will ask if ThCTL and Th17 give rise to committed memory subsets and determine their roles in combatting influenza. To accomplish these aims we will: 1) Isolate defined CD4 effector subsets generated in vitro and develop a scheme to separate them when they develop in vivo. We will define their cytokine and chemokine profiles, their migration and their involvement in help, cytotoxicity and protection against challenge with influenza. We will use the functional profile to develop a "signature" for each subset;2) We will determine each subset's ability to give rise to memory cells that respond to challenge and develop into secondary effectors and ask if they retain the same functional potential as they progressively differentiate;and 3) We will evaluate the mechanisms used by each memory Th subset to provide protection against lethal flu challenge. We will collaborate with: 1) Project 2 to determine which how the CD4 subsets compare with parallel CDS effector and memory subsets;2) Project 3 to determine migration of the CD4 subsets, and behavior in the lung and how interactions with selectins regulates function and memory generation from effectors;3) Project 4 to investigate whether similar Tuberculosis Ag-speeific CD4 subsets can improve protection against Tuberculosis infection.
Current vaccines for influenza are based on induction of Ab specific for coat proteins that change each year, so they provide only short term protection. Knowing the mechanisms by which memory T cells provide immunity, should suggest new CD4 T cell correlates of protection and provide insights that can be used to develop new strategies for improved vaccines, which could be targeted towards inducing robust T cell memory, in addition to antibody, so that immunization will be more effective and long lasting.
|McKinstry, K Kai; Strutt, Tara M; Bautista, Bianca et al. (2014) Effector CD4 T-cell transition to memory requires late cognate interactions that induce autocrine IL-2. Nat Commun 5:5377|
|Torrado, Egidio; Fountain, Jeffrey J; Robinson, Richard T et al. (2013) Differential and site specific impact of B cells in the protective immune response to Mycobacterium tuberculosis in the mouse. PLoS One 8:e61681|
|Hamada, Hiromasa; Bassity, Elizabeth; Flies, Amanda et al. (2013) Multiple redundant effector mechanisms of CD8+ T cells protect against influenza infection. J Immunol 190:296-306|
|Torrado, Egidio; Cooper, Andrea M (2013) Cytokines in the balance of protection and pathology during mycobacterial infections. Adv Exp Med Biol 783:121-40|
|McKinstry, K Kai; Dutton, Richard W; Swain, Susan L et al. (2013) Memory CD4 T cell-mediated immunity against influenza A virus: more than a little helpful. Arch Immunol Ther Exp (Warsz) 61:341-53|
|Brown, Deborah M; Lee, Sarah; Garcia-Hernandez, Maria de la Luz et al. (2012) Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. J Virol 86:6792-803|
|Torrado, Egidio; Cooper, Andrea M (2011) What do we really know about how CD4 T cells control Mycobacterium tuberculosis? PLoS Pathog 7:e1002196|
|Torrado, Egidio; Robinson, Richard T; Cooper, Andrea M (2011) Cellular response to mycobacteria: balancing protection and pathology. Trends Immunol 32:66-72|
|McKinstry, K K; Strutt, T M; Swain, S L (2011) Hallmarks of CD4 T cell immunity against influenza. J Intern Med 269:507-18|
|Cooper, A M; Mayer-Barber, K D; Sher, A (2011) Role of innate cytokines in mycobacterial infection. Mucosal Immunol 4:252-60|
Showing the most recent 10 out of 58 publications