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Tissue-resident T cells lose their S1P1 exit visas

Cellular & Molecular Immunology volume 11, pages 221–223 (2014)Cite this article

Kruppel-like factor 2 (KLF-2), formerly known as lung Kruppel-like factor, is a transcriptional regulator that influences the differentiation and trafficking of T cells in part by modulating the expression of CD62L, CCR7 and S1P1.6,7 During the inception of the response, as naive T cells are stimulated for the first time with their cognate antigen, KLF-2 becomes downregulated.8 This causes the loss of S1P1 (S1pr1) expression, a receptor for the chemoattractive lipid, sphingosine 1-phosphate, and leads to an accompanying increase in the surface levels of CD69, a C-type lectin which counteracts S1P1.9,10,11 These changes nurture the retention of the responding T cells within lymph nodes and allows them to receive the differentiation signals that program the response and direct their developmental fates. Eventually, the responding cells evolve and KLF-2 is re-expressed, S1P1 upregulated, CD69 extinguished and T cells are released from their secondment and allowed to disburse into the periphery. Using reporter mice in which the expression green fluorescent protein correlates with KLF-2 levels, Skon et al.5 showed that this transcription factor is expressed by memory CD8 T-cell populations in secondary lymphoid organs (the spleen and lymph nodes), but not by putative tissue-resident T cells in non-lymphoid organs including the salivary glands, brain, kidney and small intestine. This downregulation of KLF-2 expression, which occurs shortly after effector T-cell seed non-lymphoid sites, and the associated downregulation of S1pr1, are vital steps for preventing the egress of the developing tissue-resident pool.

Inspection of the dynamics of KLF-2 expression by lymphocytic choriomeningitis virus-specific CD8 T cells revealed that the levels are highest during the early effector phase of the response, at 5 days following infection, as non-lymphoid tissues first become seeded with the anti-viral T cells. KLF-2 levels then rapidly decline as the tissue-resident population matures. Studies with parabiotic mice indicated that as homeostasis is established, a small number of memory T cells can enter non-lymphoid organs; however, these visiting T cells are unique and express intermediate levels of KLF-2 and CD69, and are distinct from both the KLF-2lo, CD69hi non-recirculating tissue-resident memory T cells and the more abundant KLF-2hi, CD69lo circulating memory CD8 T cells that traffic to and equilibrate between secondary lymphoid organs. All of this evidence supports the concept that downregulation of KLF-2 is a key molecular switch that permits the establishment of tissue-resident T cells. These findings also implicate the resulting loss of S1pr1 expression, which occurs as KLF-2 declines, as a mechanism which helps to trap the T cells by limiting their ability to perceive sphingosine 1-phosphate egress signals. The importance of S1P1 is further suggested by studies using Cd69-deficient T cells. High expression of CD69 is a property shared by both recently activated T cells in lymphoid tissues as well as by tissue-resident populations in non-lymphoid organs. CD69 associates with S1P1 to block its functions and is maintained at the cell surface if S1P1 expression is ablated.11,12 Cd69−/− T cells are not efficiently retained in lymphoid tissues and also fail to establish or sustain tissue residency.5,11,13 Thus, there are striking parallels between the regulatory pathways used to retain T cells in lymph nodes during the priming phase of the response and those that sustain tissue-resident populations (Figure 1).

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Acknowledgements

We thank Shannon Kahan and Yuan Tian for helpful comments.

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  1. Department of Microbiology, University of Alabama at Birmingham, Birmingham, 35294, AL, United States

    Allan J Zajac

  2. Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, 35294, AL, United States

    Laurie E Harrington

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Zajac, A., Harrington, L. Tissue-resident T cells lose their S1P1 exit visas. Cell Mol Immunol 11, 221–223 (2014). https://doi.org/10.1038/cmi.2014.7

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