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The integration of T cell migration, differentiation and function

Key Points

  • Although the classical model of T cell entry into secondary lymphoid organs suggests that this requires CD62L, CC-chemokine receptor 7 (CCR7) and lymphocyte function-associated antigen 1 (LFA1) to support the rolling, activation and arrest of T cells at high endothelial venules, the rules are different for T cell entry in mucosal-associated lymphoid tissue, splenic white pulp and inflamed lymph nodes. T cells may also enter a lymph node downstream of a neighbouring lymph node via the afferent lymphatics. Intranodal motility is regulated by CCR7, while egress of T cells is dictated by responsiveness to sphingosine-1-phosphate (S1P) gradients.

  • Migration of activated T cells into non-lymphoid tissues may be somewhat promiscuous; however, it is influenced by developmental cues that reflect the site of T cell priming as well as the inflammatory status of the target tissue.

  • Effector T cells use various strategies to increase the efficiency of their scanning for antigen in non-lymphoid tissues. These strategies include the use of Lévy walks and adopting a 'dendritic-like' morphology in order to simultaneously contact multiple targets.

  • After pathogen clearance, memory T cells found in non-lymphoid tissues are either tissue-resident or re-circulating. Resident memory T cells adapt their phenotype in response to local cues within non-lymphoid tissues, and this may optimize site-specific protective immune responses by affecting T cell function and allowing for their long-term maintenance within these unique environments.

  • Non-lymphoid organs comprise many tissue types and compartments, each of which may be populated by different T cell subsets. Histological analyses as well as intravascular labelling of capillary-bound T cells may be necessary to place populations in their proper anatomical context.

  • The central memory T cell and effector memory T cell nomenclature suffers from an absence of universally accepted definitions. Refining these terms will be necessary for the field to optimally conceptualize and communicate the additional complexity of migration and location-dependent T cell differentiation states that have recently been characterized.

Abstract

T cells function locally. Accordingly, T cells' recognition of antigen, their subsequent activation and differentiation, and their role in the processes of infection control, tumour eradication, autoimmunity, allergy and alloreactivity are intrinsically coupled with migration. Recent discoveries revise our understanding of the regulation and patterns of T cell trafficking and reveal limitations in current paradigms. Here, we review classic and emerging concepts, highlight the challenge of integrating new observations with existing T cell classification schemes and summarize the heuristic framework provided by viewing T cell differentiation and function first through the prism of migration.

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Figure 1: T cell recirculation through lymph nodes.
Figure 2: Location dictates homing and differentiation in two discrete phases.
Figure 3: Means by which T cells within non-lymphoid tissues increase their efficiency of immunosurveillance and pathogen control.
Figure 4: Location dictates the rapidity by which memory T cells contribute to protection.
Figure 5: Tissue architecture considerations for T cell trafficking, subsets and analyses of isolated populations.
Figure 6: Anatomic compartmentalization of representative tissues where T cells may be sampled.

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Acknowledgements

The authors thank V. Vezys and S. Jameson (University of Minnesota) for helpful discussion. This study was supported by US National Institutes of Health (NIH) grant R01AI084913-01 (to D.M.), NIH grant T32AI007313 (to J.M.S.) and the Office Of The Director, NIH, under Award Number DP2OD006467 (to D.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Masopust, D., Schenkel, J. The integration of T cell migration, differentiation and function. Nat Rev Immunol 13, 309–320 (2013). https://doi.org/10.1038/nri3442

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