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Murine Neonatal CD4⁺ Cells Are Poised for Rapid Th2 Effector-Like Function¹

Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136

Murine neonates typically mount Th2-biased immune responses. This entails a cell-intrinsic component whose molecular basis is unknown. We found that neonatal CD4⁺ T cells are uniquely poised for rapid Th2 function. Within 24 h of activation, neonatal CD4⁺ cells made high levels of IL-4 and IL-13 mRNA and protein. The rapid high-level IL-4 production arose from a small subpopulation of cells, did not require cell cycle entry, and was unaffected by pharmacologic DNA demethylation. CpG methylation analyses in resting neonatal cells revealed pre-existing hypomethylation at a key Th2 cytokine regulatory region, termed conserved noncoding sequence 1 (CNS-1). Robust Th2 function and increased CNS-1 demethylation was a stable property that persisted in neonatal Th2 effectors. The transcription factor STAT6 was not required for CNS-1 demethylation and this state was already established in neonatal CD4 single-positive thymocytes. CNS-1 demethylation levels were much greater in IL-4-expressing CD4 single-positive thymocytes compared with unactivated cells. Together, these results indicate that neonatal CD4⁺ T cells possess distinct qualities that could predispose them toward rapid, effector-like Th2 function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health (NIH) Grant R01 AI44923-02 (to B.A.) and NIH National Research Service Award 1F30 ES012850-01 (to S.R.).

² Address correspondence and reprint requests to Dr. Becky Adkins, Department of Microbiology and Immunology R-138, 1600 NW 10th Avenue, Rosenstiel Medical Science Building Room 3152A, Miller School of Medicine, University of Miami, Miami, FL 33136. E-mail address: radkins{at}med.miami.edu

³ Abbreviations used in this paper: LCR, locus control region; CNS-1, conserved noncoding sequence 1; SP, single positive; CS-1, consensus sequence 1; RHS, rad50 hypersensitivity site; LIP, lymphopenia-induced proliferation.