Understanding mechanisms that regulate memory in T cells is crucial for developing strategies to protect against epidemic and pandemic influenza viruses. The goal of this project is to determine the contribution of the selectin family of adhesion molecules (E, P, and L) and the selectin ligand, PSGL-1, to T cell memory Recently, we found that glycosylated, biologically active ligands for selectins are acquired by a subset of CD4 and CD8 effectors in the draining lymph nodes after influenza virus infection and represent the majority of responding T cells in the lungs including IFN-g or IL-17 producers, in vivo correlates of Th1 and Th17 cells, respectively. Moreover, we find that a consistent fraction of memory phenotype T cells express selectin-binding activity, suggesting that this is a stable heritable trait that distinguishes a subset of memory cells. In the absence of functional selectin ligands or PSGL-1, CD4 cell expansion and localization in the lungs after influenza virus infection is unaltered. However, CD4 effectors produce elevated levels of IFN-g and IL-17 suggesting a role for selectin ligands in dampening the effector response. Importantly, the development of memory CD4 cells with the capacity for secondary expansion after infection is impaired, possibly because of altered homeostatic regulation. Our data support the hypothesis that mechanisms regulated by selectins can be essential for the delivery of signals that control CD4 effector cell responses as well as the homeostatic maintenance of a subset of memory cells. We will investigate the novel function(s) of selectins in the regulation of effector and memory T cells in following specific Aims: 1) to determine if differences in selectin-binding capacity identify memory T cell subsets with distinct functional properties and homeostatic regulation;2) to investigate selectin-dependent responses of T cells and the role of selectin- binding capacity in the generation of memory cells after influenza virus infection;and 3) to identify mechanisms by which selectins regulate T cell homeostasis. We will take advantage of mice that are deficient in PSGL-1-/-, mice that lack PSGL-1 signaling, and mice that lack functional selectin ligands due to deficiency of the IV/VII fucosyl transferases. We will use IFN-g and IL-17 reporter mice, selectin ligand fusion proteins, and WT and engineered influenza viruses to enable us to assess the responses of polyclonal and TCR transgenic CD4 cells and make comparisons to CDS cells. In each of these Aims we will collaborate with Projects 1 and 2 to examine defined subsets of CD4 and CD8 cells in the influenza model. We will collaborate with project 4, which will determine the relevance of selectins in the tuberculosis model.

Public Health Relevance

These studies together with those of projects 1, 2, and 4 will investigate means by which the immune system controls pulmonary infections and will provide new insights into the regulation of the development and homeostasis of memory T cells through mechanisms that regulate adhesion and migration that could be important for strategies to help protect the population from acute as well as chronic infections. Selectin- binding has the potential to be a new stable marker of memory T cells that have achieved effector function This would be an important breakthrough that could be extremely valuable in both clinical and basic studies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-CL-I)
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University of Massachusetts Medical School Worcester
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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
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
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Cruz, Andrea; Torrado, Egídio; 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
Sell, Stewart; Guest, Ian; McKinstry, K Kai et al. (2014) Intraepithelial T-cell cytotoxicity, induced bronchus-associated lymphoid tissue, and proliferation of pneumocytes in experimental mouse models of influenza. Viral Immunol 27:484-96
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
Jain, Nitya; Miu, Bing; Jiang, Jian-kang et al. (2013) CD28 and ITK signals regulate autoreactive T cell trafficking. Nat Med 19:1632-7

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