The maintenance of homeostatic immune surveillance and the development of effective immune responses require that leukocytes cross tissue barriers and move throughout the body, migrating in and out of the bone marrow, lymphoid and non-lymphoid tissues, under both normal and infected or inflamed conditions. The efficient trafficking of activated effector T cells into peripheral non-lymphoid tissues is key to enact their protective functions. Insufficient T cell activity contributes to impaired local adaptive immunity, recurrent infections and delayed wound healing, whereas excessive T cell recruitment leads to an exaggerated inflammatory response and the associated tissue damage. Despite considerable advances in the understanding of T cell trafficking in secondary lymphoid organs, the real-time recruitment of T cells into inflamed tissues is not well characterized. Successful early local innate immune response is critical for elicitation of T cell effector functions at the peripheral tissue sites. Therefore, it is likely that the type of innate cells, mode of early innate responses, and associated local inflammatory mediators will all impact on the molecular mechanisms by which effector T cells successfully move into the inflamed tissues. Our preliminary data showed that migrating neutrophils leave membrane trails into the influenza-infected trachea. The trail contains high level of chemokine CXCL12, which enhances effector CD8 T cell migration. In this study, we hypothesize that the diversity in the local tissue milieus created by the early innate responses provides a combinatorial mechanism for generating both specificity and flexibility in T cell-endothelial cell interactions and transmigration in vivo. We will investigate; (1) whether the neutrophil trails provide highly localized haptotactic chemical signals to guide the subsequent recruitment of effector T cells? (2) if signals from the neutrophil trails influence local inflammatory chemokines and regulate the tissue-specific homing of effector T cells, and (3) the effects of the local inflammatory cytokine TNF-a on integrin activation in effector T cells and their migration. Understanding how to control effector T cell homing through the manipulation of local tissue environments has potential applications in many chronic inflammatory settings.

Public Health Relevance

T cells are abundantly present in the sites of autoimmune disease and chronic inflammation, where they produce a wide array of cytokines that can exert pro-inflammatory effects. Therefore, recruitment of T cells to the inflammation sites has emerged as a key factor in the pathogenesis of the inflammatory diseases. This study will determine the molecular mechanisms that regulate T cell migration, which would lead to the design of a novel therapeutic approach to treat the chronic inflammatory disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI102851-04
Application #
9284405
Study Section
Special Emphasis Panel (ZAI1-LGR-I)
Project Start
Project End
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
4
Fiscal Year
2017
Total Cost
$363,279
Indirect Cost
$126,615
Name
University of Rochester
Department
Type
Domestic Higher Education
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Walling, Brandon L; Kim, Minsoo (2018) LFA-1 in T Cell Migration and Differentiation. Front Immunol 9:952
Kim, Hye-Ran; Mun, YeVin; Lee, Kyung-Sik et al. (2018) T cell microvilli constitute immunological synaptosomes that carry messages to antigen-presenting cells. Nat Commun 9:3630
Topham, David J; Reilly, Emma C (2018) Tissue-Resident Memory CD8+ T Cells: From Phenotype to Function. Front Immunol 9:515
Oakes, Patrick W; Fowell, Deborah J (2018) CCR7 fuels and LFA-1 grips. Nat Immunol 19:516-518
Batchu, Sri N; Dugbartey, George J; Wadosky, Kristine M et al. (2018) Innate Immune Cells Are Regulated by Axl in Hypertensive Kidney. Am J Pathol 188:1794-1806
DiPiazza, Anthony; Laniewski, Nathan; Rattan, Ajitanuj et al. (2018) CD4 T Cell Epitope Specificity and Cytokine Potential Are Preserved as Cells Transition from the Lung Vasculature to Lung Tissue following Influenza Virus Infection. J Virol 92:
Oakes, Patrick W (2018) Balancing forces in migration. Curr Opin Cell Biol 54:43-49
Jones, Jason S; Small, David M; Nishimura, Nozomi (2018) In Vivo Calcium Imaging of Cardiomyocytes in the Beating Mouse Heart With Multiphoton Microscopy. Front Physiol 9:969
Kim, Kyun-Do; Bae, Seyeon; Capece, Tara et al. (2017) Targeted calcium influx boosts cytotoxic T lymphocyte function in the tumour microenvironment. Nat Commun 8:15365
Nogales, Aitor; Martinez-Sobrido, Luis; Topham, David J et al. (2017) NS1 Protein Amino Acid Changes D189N and V194I Affect Interferon Responses, Thermosensitivity, and Virulence of Circulating H3N2 Human Influenza A Viruses. J Virol 91:

Showing the most recent 10 out of 25 publications