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Different patterns of peripheral migration by memory CD4+ and CD8+ T cells


Infections localized to peripheral tissues such as the skin result in the priming of T-cell responses that act to control pathogens. Activated T cells undergo migrational imprinting within the draining lymph nodes1, resulting in memory T cells that provide local and systemic protection2. Combinations of migrating and resident memory T cells have been implicated in long-term peripheral immunity, especially at the surfaces that form pathogen entry points into the body3. However, T-cell immunity consists of separate CD4+ helper T cells and CD8+ killer T cells, with distinct effector and memory programming requirements4. Whether these subsets also differ in their ability to form a migrating pool involved in peripheral immunosurveillance or a separate resident population responsible for local infection control has not been explored. Here, using mice, we show key differences in the migration and tissue localization of memory CD4+ and CD8+ T cells following infection of the skin by herpes simplex virus. On resolution of infection, the skin contained two distinct virus-specific memory subsets; a slow-moving population of sequestered CD8+ T cells that were resident in the epidermis and confined largely to the original site of infection, and a dynamic population of CD4+ T cells that trafficked rapidly through the dermis as part of a wider recirculation pattern. Unique homing-molecule expression by recirculating CD4+ T effector-memory cells mirrored their preferential skin-migratory capacity. Overall, these results identify a complexity in memory T-cell migration, illuminating previously unappreciated differences between the CD4+ and CD8+ subsets.

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Figure 1: Killer and helper memory T cells localize to different areas in the skin and display distinct migration patterns.
Figure 2: Migratory differences between helper and killer memory T cells.
Figure 3: Imprinting of ESL and PSL expression in memory T cells.
Figure 4: Migrational imprinting mirrors immunosurveillance function by memory helper T cells.

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We thank members of the Carbone and Heath laboratories for discussions. This work was supported by the Australian NHMRC and ARC.

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Authors and Affiliations



T.G., W.R.H., F.R.C. and S.N.M. designed the study. T.G., A.Z., L.K.M. and S.N.M. performed experiments. T.G., A.Z. and S.N.M. collected and analysed data. P.G.W. and A.G.B. provided reagents and gave conceptual advice. F.R.C. wrote the manuscript with T.G., W.R.H. and S.N.M. The research program was led by F.R.C. and W.R.H. who are joint senior authors.

Corresponding authors

Correspondence to Thomas Gebhardt or Scott N. Mueller.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-10 with legends, and Supplementary Movie legends 1-6. (PDF 4454 kb)

Supplementary Movie 1

This movie shows the migration of effector CD8+ T cells and CD4+ T cells in the epidermis and dermis of the skin 8 days after HSV skin infection of mice (see Supplementary Information file for full legend). (MOV 4182 kb)

Supplementary Movie 2

This movie demonstrates the migratory tracks of effector CD8+ T cells and CD4+ T cells in the epidermis and dermis of the skin 8 days after HSV skin infection (see Supplementary Information file for full legend). (MOV 5974 kb)

Supplementary Movie 3

This movie shows the differential localisation of memory CD8+ T cells in the epidermis and memory CD4+ T cells in the dermis of the skin after HSV skin infection. The dendritic morphology and low speed migration of the epidermal CD8+ T cells is evident alongside rapidly migrating dermal CD4+ T cells (see Supplementary Information file for full legend). (MOV 2409 kb)

Supplementary Movie 4

This movie further demonstrates the differential localization and migration by memory CD8+ T cells in the epidermis and memory CD4+ T cells in the dermis of the skin after HSV skin infection (see Supplementary Information file for full legend). (MOV 3284 kb)

Supplementary Movie 5

This movie shows the tracking of memory CD8+ and CD4+ T cells in the skin after HSV skin infection, and further highlights the dendritic morphology and low speed migration of the epidermal CD8+ T cells (see Supplementary Information file for full legend). (MOV 5329 kb)

Supplementary Movie 6

This movie demonstrates that memory CD4+ T cells continue to migrate dynamically through skin, at sites distal to the infection (see Supplementary Information file for full legend). (MOV 2254 kb)

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Gebhardt, T., Whitney, P., Zaid, A. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).

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