CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help - PubMed (original) (raw)

CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help

Yusuke Nakanishi et al. Nature. 2009.

Abstract

CD4(+) T helper cells are well known for their role in providing critical signals during priming of cytotoxic CD8(+) T lymphocyte (CTL) responses in vivo. T-cell help is required for the generation of primary CTL responses as well as in promoting protective CD8(+) memory T-cell development. However, the role of CD4 help in the control of CTL responses at the effector stage is unknown. Here we show that fully helped effector CTLs are themselves not self-sufficient for entry into the infected tissue, but rely on the CD4(+) T cells to provide the necessary cue. CD4(+) T helper cells control the migration of CTL indirectly through the secretion of IFN-gamma and induction of local chemokine secretion in the infected tissue. Our results reveal a previously unappreciated role of CD4 help in mobilizing effector CTL to the peripheral sites of infection where they help to eliminate infected cells.

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Figures

Figure 1

Figure 1. CD4 help is required for CTL migration into the vaginal mucosa after HSV-2 infection

(a) Naïve congenic 2 × 105 gBT-I cells were transferred into WT mice. Six days after TK− HSV-2 vaginal infection, 2 × 106 effector gBT-I cells isolated from these mice were transferred into secondary hosts (some treated with anti-IFN-γ Ab) infected with TK− HSV-2 3.5 days earlier. Numbers of gBT-I cells in the indicated tissues (b–f) were assessed 5 days post infection. The data are pooled from two independent experiments and presented as mean ± SEM (n = 5 – 6 mice per group). **, p < 0.01.

Figure 2

Figure 2. CD4 T cell-secreted IFN-γ mediates CTL entry into infected vaginal tissue

(a) HSV-primed WT or IFN-γ−/− CD4+ T cells (107) were adoptively transferred into CD4−/− (b–e) or IFNγ−/− mice (f–i) at 2.5 days post HSV-2 ivag infection. One day later, fully helped congenic effector gBT-I (2 × 106) cells were transferred into these mice. Five days after infection, the number of gBT-I cells in the indicated tissues was analyzed (b–i). Results are mean ± SEM (n = 4) and are representative of four independent experiments. Statistics were determined by unpaired two-tailed t-test. *, p < 0.05. **, p < 0.01.

Figure 3

Figure 3. CTL recruitment to the infected tissue depends on CXCR3

Recipient mice were reconstituted with 105 WT or CXCR3−/− gBT-I cells. (a) At 3.5 days post infection, division of WT (blank), CXCR3−/− (filled), and uninfected (gray) gBT-I cells in the draining lymph nodes was analyzed. Numbers of total CD4+ T cells within the vagina (b) and gBT-I cells in the indicated tissues (c–f) were analyzed on day 6 post infection. (g) Vaginal tissues 7 days after infection were stained for gBT-I cells (red) and nuclei (blue). Arrows; basement membrane, yellow; vaginal lumen, white. Results are mean ± SEM (n = 4). Data are representative of three separate experiments. *, p < 0.05.

Figure 4

Figure 4. Secretion of CTL-recruiting chemokines in the infected tissue depends on CD4 T help

Four days after HSV-2 infection, vaginal wash was collected from WT, CD4−/− mice or mice that were treated with anti-IFN-γ Ab on day 3 p.i. (as in Fig. 1a). Cytokine and chemokine concentrations were determined by Luminex bead assay. Data were pooled from two independent experiments (n = 6) and represented as mean ± SEM. *, p < 0.05; **, p < 0.01 (one-way ANOVA followed by Tukey’s post-hoc multiple comparison).

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