Skin Effector Memory T Cells Do Not Recirculate and Provide Immune Protection in Alemtuzumab-Treated CTCL Patients

Abstract

CTCL is a cancer of skin homing T cells with variants that include leukemic CTCL (L-CTCL), a malignancy of central memory T cells (TCM), and mycosis fungoides (MF), a malignancy of skin resident effector memory T cells (TEM). We report that low-dose alemtuzumab (αCD52) effectively treated patients with refractory L-CTCL but not MF. Alemtuzumab depleted all T cells in blood and depleted both benign and malignant TCM from skin, but a diverse population of skin resident TEM remained in skin after therapy. T-cell depletion with alemtuzumab required the presence of neutrophils, a cell type frequent in blood but rare in normal skin. These data suggest that TCM were depleted because they recirculate between the blood and skin whereas skin resident TEM were spared because they are sessile and non-recirculating. After alemtuzumab treatment, skin T cells produced lower amounts of IL-4 and higher amounts of IFNγ. Moreover, there was a marked lack of infections in alemtuzumab-treated L-CTCL patients despite the complete absence of T cells in blood, suggesting that skin resident TEM can protect the skin from pathogens even in the absence of T cell recruitment from the circulation. Together, these data suggest that alemtuzumab may treat refractory L-CTCL without severely compromising the immune response to infection by depleting circulating TCM but sparing the skin resident TEM that provide local immune protection of the skin.

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

“…However, the possibility of migration to the draining LN (but not recirculation to other tissues) following Ag stimulation was not excluded, especially for CD4 + T cells, and indeed, it is reported that some patients with malignant disease of effector memory T cells (mycosis fungoides) can develop LN involvement (28). Our data confirm that the majority of skin-tropic T cells in the blood during noninflammatory conditions are of the central memory type.…”

“…Evidence from murine experiments and studies of T cell depletion in human skin T cell malignancies (leukemic CTCL and mycosis fungoides) suggest that central memory T cells from skin regularly recirculate, whereas this is not the case for skin effector memory cells (28,29). However, the possibility of migration to the draining LN (but not recirculation to other tissues) following Ag stimulation was not excluded, especially for CD4 + T cells, and indeed, it is reported that some patients with malignant disease of effector memory T cells (mycosis fungoides) can develop LN involvement (28).…”

Dermal Regulatory T Cells Display Distinct Migratory Behavior That Is Modulated during Adaptive and Innate Inflammation

“…These findings are somewhat difficult to reconcile with the present finding that only a small proportion of the dermal Tregs are actively migratory. Recent studies in humans and mice provide evidence that the skin is a major reservoir of nonrecirculating, resident effector memory T cells (9,(31)(32)(33). These resident cells are thought to serve important functions in controlling local immune responses.…”

Differential Reconstitution of T Cell Subsets following Immunodepleting Treatment with Alemtuzumab (Anti-CD52 Monoclonal Antibody) in Patients with Relapsing–Remitting Multiple Sclerosis

“…However, they subsequently underwent a rapid homeostatic proliferation, which at month 1 led to an increased percentage of CD4 + and CD8 + memory cells in comparison with baseline. Following nearly complete depletion, memory cells preferentially expanded owing to their homeostatic proliferation, the conversion of naive cells to the memory phenotype, decreased requirements for high Ag dose and costimulatory signals for activation, as well as preferential survival in peripheral lymphoid organs from which they can repopulate the peripheral circulation (32,33).…”