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 Thi and Thi7 participate in an effective immune response. We will compare ThCTL to Thi7 and Thi 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 Thi7 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 migrafion 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 TuberculosisAg-speeific CD4 subsets can improve protecfion against Tuberculosis infecfion.

Public Health Relevance

Current vaccines for influenza are based on induction of Ab specific for coat proteins that change each year, so they provide only short term protecfion. 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 longlasting.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-CL-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
United States
Zip Code
Marshall, Nikki B; Vong, Allen M; Devarajan, Priyadharshini et al. (2017) NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection. J Immunol 198:1142-1155
Strutt, T M; Dhume, K; Finn, C M et al. (2017) IL-15 supports the generation of protective lung-resident memory CD4 T cells. Mucosal Immunol :
Swain, Susan L; Kugler-Umana, Olivia; Kuang, Yi et al. (2017) The properties of the unique age-associated B cell subset reveal a shift in strategy of immune response with age. Cell Immunol 321:52-60
Strutt, Tara M; McKinstry, Karl Kai; Kuang, Yi et al. (2016) Direct IL-6 Signals Maximize Protective Secondary CD4 T Cell Responses against Influenza. J Immunol 197:3260-3270
Tinoco, Roberto; Carrette, Florent; Barraza, Monique L et al. (2016) PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion. Immunity 44:1190-203
Bautista, Bianca L; Devarajan, Priyadharshini; McKinstry, K Kai et al. (2016) Short-Lived Antigen Recognition but Not Viral Infection at a Defined Checkpoint Programs Effector CD4 T Cells To Become Protective Memory. J Immunol 197:3936-3949
Brodeur, Tia Y; Robidoux, Tara E; Weinstein, Jason S et al. (2015) IL-21 Promotes Pulmonary Fibrosis through the Induction of Profibrotic CD8+ T Cells. J Immunol 195:5251-60
Torrado, Egidio; Fountain, Jeffrey J; Liao, Mingfeng et al. (2015) Interleukin 27R regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection. J Exp Med 212:1449-63
Cruz, Andrea; Torrado, EgĂ­dio; Carmona, Jenny et al. (2015) BCG vaccination-induced long-lasting control of Mycobacterium tuberculosis correlates with the accumulation of a novel population of CD4?IL-17?TNF?IL-2? T cells. Vaccine 33:85-91
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

Showing the most recent 10 out of 84 publications