CD27 sustains survival of CTLs in virus-infected nonlymphoid tissue in mice by inducing autocrine IL-2 production
Victor Peperzak, … , Elise A.M. Veraar, Jannie Borst
Victor Peperzak, … , Elise A.M. Veraar, Jannie Borst
Published December 1, 2009
Citation Information: J Clin Invest. 2010;120(1):168-178. https://doi.org/10.1172/JCI40178.
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Research Article Immunology

CD27 sustains survival of CTLs in virus-infected nonlymphoid tissue in mice by inducing autocrine IL-2 production

Abstract

Immunity to infections relies on clonal expansion of CD8+ T cells, their maintenance as effector CTLs, and their selection into a memory population. These processes rely on delivery of survival signals to activated CD8+ T cells. We here reveal the mechanism by which costimulatory CD27-CD70 interactions sustain survival of CD8+ effector T cells in infected tissue. By unbiased genome-wide gene expression analysis, we identified the Il2 gene as the most prominent CD27 target gene in murine CD8+ T cells. In vitro, CD27 directed IL-2 expression and promoted clonal expansion of primed CD8+ T cells exclusively by IL-2–dependent survival signaling. In mice intranasally infected with influenza virus, Cd27–/– CD8+ effector T cells displayed reduced IL-2 production, accompanied by impaired accumulation in lymphoid organs and in the lungs, which constitute the tissue effector site. Reconstitution of Cd27–/– CD8+ T cells with the IL2 gene restored their accumulation to wild-type levels in the lungs, but it did not rescue their accumulation in lymphoid organs. Competition experiments showed that the IL-2 produced under the control of CD27 supported effector CD8+ T cell survival in the lungs in an autocrine manner. We conclude that CD27 signaling directs the IL-2 production that is reportedly essential to sustain survival of virus-specific CTLs in nonlymphoid tissue.

Authors

Victor Peperzak, Yanling Xiao, Elise A.M. Veraar, Jannie Borst

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Figure 6

IL-2 rescues survival of virus-specific Cd27–/– CD8+ T cells at the tissue site.

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IL-2 rescues survival of virus-specific Cd27–/– CD8+ T cells at the tiss...
(A) Strategy: WT or Cd27–/– influenza virus–specific F5 T cells were retrovirally transduced in vitro with a vector encoding IL-2IRESGFP or with an empty vector (ev) encoding YFP or GFP only. Transduced F5 T cells were sorted for CD8 and GFP or YFP expression and injected i.v. into Cd27–/– mice, which were subsequently infected with influenza virus. At day 8, cells were harvested from DLN, spleen, and lung; enumerated; stained for CD8; and analyzed by flow cytometry. (B and C) Experimental protocol 1: WT F5 T cells with ev-YFP and Cd27–/– F5 T cells with ev-GFP were mixed at a 1:1 ratio and injected into the same recipient mice (B, left). Cd27–/– F5 T cells with IL-2IRESGFP vector were injected into different recipient mice (B, right). (B) Dot plots show the gating for transduced F5 cells as identified by GFP or YFP expression (in lung). (C) Absolute numbers of YFP+ or GFP+CD8+ of the indicated genotypes based on flow cytometry as outlined in B. (D) Experimental protocol 2: WT F5 T cells with ev-GFP and WT F5 T cells with IL-2IRESGFP vector were injected into different recipient mice. Absolute numbers of GFP+ F5 cells are shown. (E) Experimental protocol 3: WT F5 T cells with ev-YFP and Cd27–/– F5 T cells with IL-2IRESGFP vector were injected into the same recipient mice. Absolute numbers of GFP+ F5 cells are shown. Data are mean + SEM of 4 mice per group. *P < 0.05, **P < 0.01 (t test).