Expression of the CD7 Ligand K-12 in Human Thymic Epithelial Cells: Regulation by IFN-?

Abstract

CD7 is an immunoglobulin superfamily molecule expressed on T, NK, and pre-B lymphocytes. Previous studies have demonstrated a role for CD7 in T- and NK-cell activation and cytokine production. Recently, an epithelial cell secreted protein, K12, was identified as a CD7 ligand. Although CD7 is expressed intrathymically, it is not known if K12 is produced in human thymus. To determine roles that K12 might play in the human thymus, we analyzed expression of K12 in human thymocytes, thymic epithelial cells (TE), and thymic fibroblasts. We found that recombinant human K12 bound strongly to soluble hCD7, with a Keq of 37.6x10(-9) M, and this interaction was inhibited by a novel antihuman K12 monoclonal antibody (K12-A1). K12 mRNA was detected by RT-PCR and northern analysis in human TE and thymic fibroblasts, but not in human thymocytes. Expression of K12 in TE cells was upregulated by IFN-gamma. Taken together, these data demonstrated that K12 is produced by human TE cells and thymic fibroblasts, and is regulated in thymus by IFN-gamma. These data suggest a role for thymic microenvironment-produced K12 in regulation of thymocyte signaling and cytokine release, particularly in the setting of thymus pathology where IFN-gamma is upregulated such as myasthenia gravis.

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

“…In addition, cytokines may have very different roles in the thymus compared with their actions in the periphery. This expectation is consistent with the negative effect on mTEC Ins2 expression by IFN-γ which is produced in thymocytes, affects TECs [28,41] and may be important in negative selection [31,42]. This decrease was not accompanied by a decrease in the AIRE transcript, which, if anything, was upregulated.…”

“…Then, we asked whether Ins2 expression in mTECs is regulated by cytokines and whether such alterations may be mediated through effects on Aire expression. We chose to start with IFN-γ, a cytokine known to be produced in thymocytes and to have effects on TECs [28]. In addition, we explored possible effects on Ins2 expression by co-culturing mTECs with isolated primary thymocytes.…”

Secreted and Transmembrane 1A Is a Novel Co-Stimulatory Ligand

“…Co-expression of the SECTM molecules in tissues may have alternate outcomes depending on the receptors expressed by different T cells. A degree of tissue regulation of SECTM1 has been shown by Lam and colleagues who demonstrated up-regulation of SECTM1 expression in response to IFNγ by thymic epithelium [28].…”

CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies

“…15,16 CD7 provides costimulation in T cells by activating PI(3)K and PI(4)K pathways 12,13,35 on binding its ligand K12/SECTM, which is expressed by myeloid cells and thymic epithelial and stromal cells. [36][37][38] In contrast, binding of galectin-1 by CD7 can trigger apoptosis, 39 suggesting that CD7 may regulate T-cell proliferation and survival in a context-dependent manner. In our study, knocking out the CD7 gene in activated T cells did not affect their expansion or CAR-mediated cytotoxicity, suggesting that loss of CD7 is unlikely to impair the antitumor activity of CAR T cells-at least in the short term-and that costimulatory endodomains embedded in the CAR may compensate for the lack of CD7-derived costimulation.…”