SUMMARY Here, we report that kinase-dead IKKα knock-in mice develop spontaneous lung squamous cell carcinomas (SCCs) associated with IKKα downregulation and marked pulmonary inflammation. IKKα reduction upregulated the expression of p63, Trim29, and keratin 5 (K5), which serve as diagnostic markers for human lung SCCs. IKKαlowK5+p63hi cell expansion and SCC formation were accompanied by inflammation-associated deregulation of oncogenes, tumor suppressors, and stem cell regulators. Reintroducing transgenic K5.IKKα, depleting macrophages, and reconstituting irradiated mutant animals with WT bone marrow (BM) prevented SCC development, suggesting that BM-derived IKKα-mutant macrophages promote the transition of IKKαlowK5+p63hi cells to tumor cells. This mouse model resembles human lung SCCs, sheds light on the mechanisms underlying lung malignancy development, and identifies targets for therapy of lung SCCs.

Interleukin-7 (IL-7), a cytokine produced by stromal cells, is required for thymic development and peripheral homeostasis of most major subsets of T cells. We IntroductionRegulatory T (Treg) cells have a critical suppressive function for maintenance of self-tolerance and prevention of autoimmunity, 1,2 and their deficiency can predispose to gastritis, thyroiditis, diabetes and graft-versus-host disease. Initially, Treg cells were identified as a small percentage, approximately 10% to 15%, of mouse CD4 ϩ T cells that expressed CD25, the ␣ chain of IL-2R. 3,4 Treg cells also are reported to express CD45RB, 5 CD62L, 6 cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), 7-9 glucocorticoidinduced tumor necrosis factor (TNF)-like receptor (GITR), [10][11][12] CD103 (␣E␤7 integrin) 13 and forkhead box transcription factor 3 (Foxp3), an intracellular transcriptional regulator. [14][15][16] In vitro, Treg cells can block proliferative responses of both CD4 ϩ and CD8 ϩ CD25 Ϫ cells by a mechanism that remains to be clearly defined but appears to be based on cell contact and to be independent of cytokine production. [17][18][19][20][21] A very recent paper suggests Tregs suppress target cells by interleukin-2 (IL-2) deprivation and subsequent apoptosis. 22 In vivo, Treg cells suppress activation and expansion of self-reactive T cells that have escaped thymic clonal deletion. 1,3,[23][24][25] In addition to cell contact, the suppressive cytokines IL-10 and transforming growth factor (TGF)␤ have been implicated in vivo as mediators of inhibition. [26][27][28][29][30][31][32] Several studies suggest that CD4 ϩ CD25 ϩ T cells mature in the thymus as a distinct T-cell population. 5,7,10,15,29,33 High-affinity IL-2 receptors are constitutively expressed on Treg cells, and IL-2 has been implicated in the development, maintenance, and function of these cells. 34 It has been reported that IL-2 may be required for peripheral expansion and homeostasis, [35][36][37][38] and IL-2 appears to be required for Treg cell function in the periphery. 17,[39][40][41][42] Mice deficient in IL-2, IL-2R␣, or IL-2R␤ lack regulatory T cells 43,44 and develop severe autoimmune disease. 42,[45][46][47][48][49] IL-7 is a cytokine that is produced by stromal cells in lymphoid tissues and is required for development and homeostasis of most subsets of T cells. [50][51][52] The IL-7 receptor is composed of IL-7R␣ and the common cytokine receptor ␥ chain, ␥ c 53,54 . A related stromal factor, thymic stromal lymphopoietin (TSLP), also shares IL-7R␣ but additionally has a distinctive receptor subunit, TSLPR. 55,56 Naive and memory CD4 ϩ T cells require IL-7 for homeostatic survival. 57,58 In vitro it has been shown that IL-7 can, albeit less well than IL-2 or IL-4, promote the proliferation and suppressor function of CD4 ϩ CD25 ϩ cells stimulated with anti-CD3. 40 The Tr1 cell, another type of suppressor cell that acts by secreting suppressive cytokines, has been shown to respond to IL-7 in vitro. 59 It has recently been reported that Treg cells develop, s...