Tuesday, October 20, 2015

Hair follicles attract normal and lymphoma T cells via common gamma chain (γc) cytokines IL-15 and IL-7

Skin is a body's second largest surface that is continuously exposed to exogenous antigens. So, no wonder that it attracts and harbors specialized immune cells. One of these immune cells are skin resident memory T cells (TRM cells) who play an important role in local skin epidermal defense as a rapid deployment tactical units. Besides this protective function however, TRM cells can contribute to pathological conditions such a drug allergy or lymphomas.

New paper just published in Nature Medicine showed that accumulation of normal or oncogene-transformed TRM cells in skin epidermal layer is directed by hair follicle derived IL-15 and IL-7.

First, the authors confirmed that TRM cells are present in both skin dermal and epidermal layers (but CD8 T cells were present only in epidermal layer).

Next, the authors generated RAG-deficient BM chimera where the host's non-hematopoietic tissue [such as keratinocytes] also lacked IL-15 expression. Transfer of wild-type T cells into these IL-15/RAG double-deficient host showed that non-hematopoietic cell-derived IL-15 was important for CD8 T cell [but not CD4 T cell] recruitment to the epidermis [though it is not clear why would the authors suggest that non-hematopoietic tissue-specific IL-15 deficiency equals to hair follicle-specific IL-15 deficiency].

Further experiments with mice with keratinocyte-specific conditional IL-7 deletion revealed that cytokine IL-7 also played important role in recruitment of both CD4 and CD8 T cells to the skin [again, the authors have used this model as an example of hair follicle-specific IL-7 deletion. Not sure how accurate is this notion].

Accordingly, the authors showed that skin contact hypersensitivity response to hapten DNFB that requires T cell activation were reduced in mice with non-hematopoietic tissue-specific IL-15 and IL-7 deficiency.

Finally, using mouse T cell lymphoma model, that mimics human cutaneous T cell lymphoma (CTCL), the authors showed that keratinocytes-derived IL-7 was important to direct accumulation of T lymphoma cells to the epidermal layer.

In summary, this study provided mechanistic explanation for some of the clinical features of human T cell lymphomas. It appears that keratinocytes [hair follicle]-derived IL-15 and IL-7 actively attract both normal and cancerous T cells to the epidermis. Since both IL-15 and IL-7 are common gamma chain (γc) cytokines, inhibition of their signaling with JAK3 inhibitors [such as Pfizer's JAK1/3 inhibitor Tofacitinib] may provide some relieve in pathological situations such as drug [hapten]-induced allergy and T cell lymphomas (CTLC, mycosis fungoides, Sezary's syndrome).

David Usharauli

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