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Cutting Edge: CD47 Controls the In Vivo Proliferation and Homeostasis of Peripheral CD4⁺CD25⁺Foxp3⁺ Regulatory T Cells That Express CD103¹

Vu Quang Van^2,*, Jinane Darwiche^2,*, Marianne Raymond^*, Sylvie Lesage, Salim Bouguermouh^*, Manuel Rubio^* and Marika Sarfati^3,*

^* Immunoregulation, Centre Hospitalier de l’Université de Montréal, Research Center, l’Hôpital Notre-Dame, Montréal, Québec, Canada; and Hôpital Maisonneuve-Rosemont, Centre de Recherche Guy-Bernier, Montréal, Québec, Canada

Peripheral CD103⁺Foxp3⁺ regulatory T cells (Tregs) can develop both from conventional naive T cells upon cognate Ag delivery under tolerogenic conditions and from thymic-derived, expanded/differentiated natural Tregs. We here show that CD47 expression, a marker of self on hematopoietic cells, selectively regulated CD103⁺Foxp3⁺ Treg homeostasis at the steady state. First, the proportion of effector/memory-like (CD44^highCD62L^low) CD103⁺Foxp3⁺ Tregs rapidly augmented with age in CD47-deficient mice (CD47^–/–) as compared with age-matched control littermates. Yet, the percentage of quiescent (CD44^lowCD62L^high) CD103^–Foxp3⁺ Tregs remained stable. Second, the increased proliferation rate (BrdU incorporation) observed within the CD47^–/–Foxp3⁺ Treg subpopulation was restricted to those Tregs expressing CD103. Third, CD47^–/– Tregs maintained a normal suppressive function in vitro and in vivo and their increased proportion in old mice led to a decline of Ag-specific T cell responses. Thus, sustained CD47 expression throughout life is critical to avoid an excessive expansion of CD103⁺ Tregs that may overwhelmingly inhibit Ag-specific T cell responses.

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 Canadian Institute for Health and Research Grant MOP-53152. V.Q.V. and S.B. are recipients of the Canadian Institutes for health Research/Canada Graduate Scholarships Doctoral Award.

² V.Q.V. and J.D. are equal contributors to this work.

³ Address correspondence and reprint requests to Dr. Marika Sarfati, Immunoregulation, Laboratory, Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Pavillon Mailloux M4211K, 1560 Sherbrooke Street East, Montreal, Quebec H2L 4M1, Canada. E-mail address: m.sarfati{at}umontreal.ca

⁴ Abbreviations used in this paper: Treg, regulatory T cell; LN, lymph node; SLO, secondary lymphoid organ; Tg, transgenic.

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