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An obligate cell-intrinsic function for CD28 in Tregs
Ruan Zhang, … , Jonathan S. Maltzman, Laurence A. Turka
Ruan Zhang, … , Jonathan S. Maltzman, Laurence A. Turka
Published January 2, 2013
Citation Information: J Clin Invest. 2013;123(2):580-593. https://doi.org/10.1172/JCI65013.
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Research Article Immunology Article has an altmetric score of 10

An obligate cell-intrinsic function for CD28 in Tregs

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Abstract

Tregs expressing the transcription factor FOXP3 are critical for immune homeostasis. The costimulatory molecule CD28 is required for optimal activation and function of naive T cells; however, its role in Treg function has been difficult to dissect, as CD28 is required for thymic Treg development, and blockade of CD28-ligand interactions has confounding effects in trans on nonregulatory cells. To address this question, we created Treg-specific Cd28 conditional knockout mice. Despite the presence of normal numbers of FOXP3+ cells, these animals accumulated large numbers of activated T cells, developed severe autoimmunity that primarily affected the skin and lungs, and failed to appropriately resolve induced experimental allergic encephalomyelitis. This in vivo functional impairment was accompanied by dampened expression of CTLA-4, PD-1, and CCR6. Disease occurrence was not due to subversion of Cd28-deficient Tregs into pathogenic cells, as complementation with normal Tregs prevented disease occurrence. Interestingly, in these “competitive” environments, Cd28-deficient Tregs exhibited a pronounced proliferative/survival disadvantage. These data demonstrate clear postmaturational roles for CD28 in FOXP3+ Tregs and provide mechanisms which we believe to be novel to explain how interruption of CD28-ligand interactions may enhance immune responses independent of effects on thymic development or on other cell types.

Authors

Ruan Zhang, Alexandria Huynh, Gregory Whitcher, JiHoon Chang, Jonathan S. Maltzman, Laurence A. Turka

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Figure 8

Suppressive function of Cd28-ΔTregs.

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Suppressive function of Cd28-ΔTregs.
 
(A) In vitro suppression assay. S...
(A) In vitro suppression assay. Sorted WT naive cells were stimulated by soluble CD3 and T cell–depleted splenocytes with the addition of different ratios of WT Tregs or Cd28-ΔTregs. Tregs were sorted from 4-week-old mice. Teff, effector T cells. (B) In vivo colitis induction. Weight loss of Rag1–/– mice adoptively transferred with sorted CD4+CD45RBhi effector T cells with or without WT Tregs or Cd28-ΔTregs. A total of 6 mice were analyzed for each group. Data represent mean ± SEM. (C) H&E staining of the colons of mice in B. Original magnification, ×100. (D and E) Representative analysis of donor CD45.1+CD4+ effector cells and regulatory cells in the colons of mice in B. (F) Sorted WT Tregs or Cd28-ΔTregs were labeled with CellTrace Violet and adoptively transferred to Rag1–/– hosts. Lymph node cells were analyzed 7 days after transfer. Data are representative of 3 experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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