Fragility of FOXP3+ Treg phenotype

This week I am reviewing two papers dealing with different aspects of FOXP3+ Treg biology. Both papers were published in journal Cell. These are predominantly mouse works so no need to get too excited. 

1st paper was published by Dario Vignali's group (department of Immunology, University of Pittsburgh School of Medicine). They have analyzed role of Neuropilin-1 (Nrp1) in Treg phenotype in tumor context. Neuropilin-1 is a marker of thymic Tregs though this notion is not universally accepted. Interestingly, in mouse tumor model, mouse that expressed Nrp1 on half of its Tregs rejected tumor with the same vigor as mouse expressing Nrp1 on all of its Tregs. 

Furthermore, in the context of tumor challenge, Treg-specific Nrp1 deficiency drastically increased IFN-γ production in both KO and WT Tregs.

It appeared that WT Tregs required sensing of IFN-γ derived from Nrp1KO Tregs to acquire "Nrp1KO-like" phenotype. 

Finally, the authors showed that therapeutic effect of checkpoint inhibitor anti-PD1 antibody against tumor required IFN-γ sensing by Tregs.

In summary, this study showed that Nrp1 deficiency makes Tregs fragile by converting them into IFN-γ producer cells which in turn affect WT Tregs phenotype as well. The reason the authors are using term fragility rather than simply instability has to do, they claim, with the difference in FOXP3 expression between fragile and unstable Tregs. 

In a separate study, the authors showed that Treg depletion inhibits hair regrowth (after depilation). 

However, it is not clear why Tregs should be involved in such physiological process when any other innate cells could do the same.   

David Usharauli

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 (T_RM cells) who play an important role in local skin epidermal defense as a rapid deployment tactical units. Besides this protective function however, T_RM 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 T_RM cells in skin epidermal layer is directed by hair follicle derived IL-15 and IL-7.

First, the authors confirmed that T_RM 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