TGF-{beta}-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease - PubMed (original) (raw)

TGF-{beta}-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease

Riham El-Asady et al. J Exp Med. 2005.

Abstract

Destruction of the host intestinal epithelium by donor effector T cell populations is a hallmark of graft-versus-host disease (GVHD), but the underlying mechanisms remain obscure. We demonstrate that CD8(+) T cells expressing CD103, an integrin conferring specificity for the epithelial ligand E-cadherin, play a critical role in this process. A TCR transgenic GVHD model was used to demonstrate that CD103 is selectively expressed by host-specific CD8(+) T cell effector populations (CD8 effectors) that accumulate in the host intestinal epithelium during GVHD. Although host-specific CD8 effectors infiltrated a wide range of host compartments, only those infiltrating the intestinal epithelium expressed CD103. Host-specific CD8 effectors expressing a TGF-beta dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-beta activity as a critical regulating factor. Host-specific CD8 effectors deficient in CD103 expression successfully migrated into the host intestinal epithelium but were retained at this site much less efficiently than wild-type host-specific CD8 effectors. The relevance of these events to GVHD pathogenesis is supported by the finding that CD103-deficient CD8(+) T cells were strikingly defective in transferring intestinal GVHD pathology and mortality. Collectively, these data document a pivotal role for TGF-beta-dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8(+) T cells during GVHD pathogenesis.

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Figures

Figure 1.

Figure 1.

hsCD8eff infiltrate diverse host compartments during GVHD. Lethally irradiated BALB/c (H-2d) hosts were adoptively transferred with 106 SC from 2C TCR-Tg mice in combination with BMC and SC from B6 (H-2b) mice. Multicolor flow cytometry of cell suspensions with mAb 1B2 to the clonotypic 2C TCR (H-2Ld-specific) was used to identify and characterize host-specific CD8+1B2+ cells. Data shown are dot plots of 1B2 versus CD8 expression by lymphocyte populations (left) and histograms of CD44 expression by gated CD8+1B2+ lymphocytes (right; y axis, events) isolated from various host compartments at day 7 after BMT. Isotype control staining is represented by shaded histograms. Data are representative of six independent experiments.

Figure 2.

Figure 2.

Gut-specific expression of CD103 by hsCD8eff during GVHD. Lethally irradiated BALB/c (H-2d) hosts were adoptively transferred with 106 SC from 2C TCR-Tg mice in combination with BMC and SC from B6 (H-2b) mice. At the indicated time points, lymphocytes were isolated from the various host organs and subjected to four-color flow cytometry as described in the legend to Fig. 1. Data shown are histograms of CD103 expression by gated host-specific CD8+1B2+ lymphocytes (y axis, events). Isotype control staining is represented by shaded histograms. Data shown are representative of two to six independent experiments. Numbers (top) show the mean percentage (±SE) of intestinal CD8+ T cells that expressed CD103.

Figure 3.

Figure 3.

Gut-specific expression of CD103 by hsCD8eff is dependent on TGF-β activity. (A) Lethally irradiated BALB/c (H-2d) hosts were adoptively transferred with 106 SC from either 2C TCR-Tg mice expressing 2C-DNR in combination with BMC and SC from B6 (H-2b) mice. Recipients were killed at day 7 after BMT and lymphocytes infiltrating the intestinal epithelium were subjected to a three-color FACS analysis. Data shown are histograms of CD44 (left) or CD103 (right) expression by gated host-specific CD8+1B2+ (y axis, events). (B) Lethally irradiated BALB/c (H-2d) hosts were adoptively transferred with an equal mixture (0.5 × 106) of SC from wild-type 2C (Thy1.1+) and 2C-DNR (Thy1.1−) mice in combination with BMC and SC from B6 (H-2b) mice. Lymphocytes infiltrating the intestinal epithelium were isolated at the indicated time points and subjected to a three-color FACS analysis. (left) dot plot shows Thy1.1 and 1B2 expression by gated CD8+ lymphocytes. (right) histograms show the percentage of CD103 expression by gated host-specific CD8+1B2+ cells of either a wild-type 2C (top, Thy1.1+1B2+ cells) or 2C-DNR (bottom, Thy1.1−1B2+ cells) origin (y axis, events). Isotype control staining is indicated by shaded histograms. Results are representative of three independent experiments.

Figure 4.

Figure 4.

CD103 expression promotes retention of hsCD8eff in the host intestinal epithelium. Lethally irradiated BALB/c (H-2d) hosts were adoptively transferred with an equal mixture (0.5 × 106) of SC from wild-type 2C (Thy1.11) and 2C-CD1032/2 (Thy1.12) mice in combination with BMC and SC from B6 (H-2b) mice. Lymphocytes infiltrating host organs were isolated at the indicated time points and subjected to a three-color FACS analysis. (A) Dot plots of Thy1.1 versus 1B2 expression by gated CD81 lymphocytes isolated from the intestinal epithelium (top) or spleen (bottom) at the indicated time points. (B) Dot plots of Thy1.1 versus 1B2 expression by gated CD8+ lymphocytes isolated from the indicated organs at day 28 after BMT. Numbers in quadrants denote the corresponding percentages among gated CD8+ T cells.

Figure 5.

Figure 5.

Properties of wild-type and CD103−/− host-specific CD8 cells that infiltrate the host intestinal epithelium during GVHD. (A–E) Lethally irradiated BALB/c (H-2d) hosts were adoptively transferred with an equal mixture (0.5 × 106) of SC from wild-type 2C (Thy1.1+) and 2C-CD103−/− (Thy1.1−) mice in combination with BMC and SC from B6 (H-2b) mice. Recipients were killed at the indicated time points and lymphocytes infiltrating various host organs were subjected to a three-color FACS analysis. Data shown are the expression of CD11a (A), CD62L (B), TNF-α (C), IFN-γ (D), and Annexin-V (E) by wild-type (left) or CD103−/− (right) host-specific CD8 cells (gated Thy1.1+1B2+ or Thy1.1−1B2+ cells, respectively) isolated from the intestinal epithelium at day 6. Shaded histograms represent isotype control staining. Results are representative of two to three independent experiments. (F) Equal numbers of CFSE-labeled splenic T cells from wild-type (Thy1.1+) and CD103−/− (Thy1.1−) 2C mice were transferred into lethally irradiated BALB/c mice in combination with BMC and SC from B6 (H-2b) mice. Lymphocytes were harvested from the intestine at day 6 after BMT and analyzed by four-color flow cytometry. Data shown are CSFE fluorescence by wild-type (left) or CD103−/− (right) host-specific CD8 cells (gated Thy1.1+1B2+ or Thy1.1−1B2+ cells, respectively) isolated from the intestinal epithelium. Shaded histograms show CSFE fluorescence at day 0. Y axis, events.

Figure 6.

Figure 6.

CD103 expression promotes destruction of the host intestinal epithelium by CD8**+** T cells during GVHD. Lethally irradiated BALB/c (H-2d) hosts were adoptively transferred with 10 × 106 B6 BMC alone or in combination with 10 × 106 CD8-enriched SC from either wild-type or CD103−/− mice on the B6 (H-2b) background. (A) Survival of recipients of B6 BMC alone (dashed line, n = 4), or in combination with CD8+ T cells from wild-type (dotted line; MST = 8.2 ± 0.8 d, n = 11) or CD103−/− (continuous line; MST > 48.6 ± 6.5 d, n = 10) donors (P < 0.001). (B) Representative H&E sections of intestinal specimens at day 14 after BMT from recipients of wild-type (left) or CD103−/− (right) CD8+ T cells, at low (top, 20×) and high (bottom, 40×) magnification. Arrows denote apoptotic bodies. (C) Representative H&E sections of liver specimens at day 14 after BMT in recipients of wild-type (left) or CD103−/− (right) CD8+ T cells (magnification, 20×).

Figure 7.

Figure 7.

Expression of CD103 by polyclonal CD8 effectors infiltrating the host intestinal epithelium during GVHD. Lethally irradiated BALB/c (H-2d) hosts were adoptively transferred with 10 × 106 B6 BMC and 10 × 106 CD8-enriched SC from either wild-type (right) or CD103−/− (left) B6 (H-2b) mice. Lymphocytes were isolated from the host intestinal epithelium at the indicated times and subjected to four-color FACS analyses using FITC-conjugated mAb to H-2Kb in combination with anti–CD8-PerCP, anti–CD103-PE, and anti–CD44-APCs. Data shown are dot plots of CD103 versus CD8 expression by gated donor (H-2Kb+) lymphocytes infiltrating the host intestinal epithelium. Donor CD8+ T cells were uniformly CD44hi, consistent with a CD8 effector phenotype (not depicted). Results are representative of two independent experiments. Numbers in quadrants denote the percentage of total cells within that area.

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