Blockade of CD122 on memory T cells in the skin suppresses sclerodermatous graft-versus-host disease

Abstract

Background: Antigen-stimulated naïve T cells differentiate into effector and memory T cells, of which resident memory T (T_RM) cells reside permanently in organ tissues. Involvement of T_RM cells has been indicated in pathological conditions of various skin diseases. CD122, which is the β chain subunit of interleukin (IL)- 2 and IL-15 receptors, is expressed on immune cells including T_RM cells.

Objective: To investigate whether CD122 signaling in skin CD8⁺ T_RM cells mediates the development of mucocutaneous graft-versus-host disease (GVHD).

Methods: We used a genetically modified mouse expressing a membrane-bound form of chicken ovalbumin (OVA) under the control of the keratin 14 promoter, which develops GVHD-like erosive mucocutaneous disease resulting in sclerodermatous disease after transfer of OVA-specific T cell-receptor-transgenic CD8⁺ OT-I cells. Mice with mucocutaneous GVHD were treated with an anti-CD122 blocking antibody.

Results: Administration of an anti-CD122 blocking antibody suppresses the development of acute/chronic GVHD-like mucocutaneous disease in our murine model via the reduction of CD122-expressing memory CD8⁺ T cells, including skin, memory autoaggressive CD8⁺ T cells. Moreover, blockade of CD122, even after the establishment of acute GVHD, inhibited the development of chronic GVHD-like sclerodermatous disease via the reduction of epidermal and dermal T_RM autoaggressive CD8⁺ T cells.

Conclusion: Skin memory CD8⁺ T cells in particular mediate the development of mucocutaneous GVHD, and blockade of CD122 may be an effective treatment strategy, especially for sclerodermatous GVHD.

Keywords: Antibody; CD122; CD8(+) T cell; Interleukin-15; Interleukin-2; Mucocutaneous graft-versus-host disease; Resident memory T cell.