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. 2011 Dec 1;118(23):6209-19.
doi: 10.1182/blood-2011-01-330035. Epub 2011 Jul 18.

A repertoire-independent and cell-intrinsic defect in murine GVHD induction by effector memory T cells

Kathryn W Juchem  1 , Britt E Anderson, Cuiling Zhang, Jennifer M McNiff, Anthony J Demetris, Donna L Farber, Andrew J Caton, Warren D Shlomchik, Mark J Shlomchik
Affiliations

A repertoire-independent and cell-intrinsic defect in murine GVHD induction by effector memory T cells

Kathryn W Juchem et al. Blood. .

Abstract (VSports最新版本)

Effector memory T cells (T(EM)) do not cause graft-versus-host disease (GVHD), though why this is has not been elucidated. To compare the fates of alloreactive naive (T(N)) or memory (T(M)) T cells, we developed a model of GVHD in which donor T cells express a transgene-encoded TCR specific for an antigenic peptide that is ubiquitously expressed in the recipient. Small numbers of naive TCR transgenic (Tg) T cells induced a robust syndrome of GVHD in transplanted recipients. We then used an established method to convert TCR Tg cells to T(M) and tested these for GVHD induction. This allowed us to control for the potentially different frequencies of alloreactive T cells among T(N) and T(M), and to track fates of alloreactive T cells after transplantation. T(EM) caused minimal, transient GVHD whereas central memory T cells (T(CM)) caused potent GVHD. Surprisingly, T(EM) were not inert: they, engrafted, homed to target tissues, and proliferated extensively, but they produced less IFN-γ and their expansion in target tissues was limited at later time points, and local proliferation was reduced. Thus, cell-intrinsic properties independent of repertoire explain the impairment of T(EM), which can initiate but cannot sustain expansion and tissue damage. VSports手机版.

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Figure 1
Figure 1
A TCR Tg model of GVHD. (A-B) HA104 mice received 750cGy and 8 × 106 BALB/c RAG−/− BM cells alone or in combination with 9000, 3000, or 1000 sorted TS1 TN. As an additional control, wt mice received BM cells in combination with 3000 TN. Shown are survival (A) and weight loss (B). P values are relative to BM only controls. Data are representative of 2 independent experiments. (C-D) HA104 mice received 750cGy and 8 × 106 RAG−/− BM cells alone or in combination with 3000 sorted TS1 TN. On day 21, mice were killed and tissues were taken for histopathology analysis. Representative skin, colon, and liver pathology are shown in panel C. Pathology scores are shown in panel D. Pathology data were combined from 2 independent experiments.
Figure 2
Figure 2
Generation of TS1 memory cells. TS1 TN were stimulated in vitro with HA peptide and irradiated T cell-depleted splenocytes for 3 days. Cells were then transferred into RAG−/− mice and allowed to rest for 2-3 months (design, A). Shown are representative flow cytometry showing the phenotypes before culture (B), after 3 days in culture (C) and after resting in RAG−/− mice (D). Data are representative of > 10 experiments. IFN-γ production in TN, TCM and TEM post stimulation with PMA and ionomycin is shown in panel E (data are from 1 experiment).
Figure 3
Figure 3
TS1 TN and TCM cause severe GVHD whereas TS1 TEM cause only mild GVHD. HA104 mice received 750cGy and 8 × 106 RAG−/− BM cells alone or in combination with 9000 or 3000 TS1 TN, TCM or TEM. Mice were killed at day 60 and tissues were taken for histopathologic analysis. Survival and weight loss are shown in panel A. P < .0001 comparing weight loss in recipients of TN or TCM vs recipients of BM alone on days 7 to 60. P < .0001 comparing weight loss in TEM vs TN recipients on days 13-60. P < .0001 on days 9-23 and P < .05 on days 46-60 comparing weight loss in recipients of 9000 TEM vs recipients of BM alone. Weight data in recipients of 3000 TS1 cells are representative of > 3 independent experiments; weight loss in recipients of 9000 TS1 TEM is from one experiment. Mice were killed at the conclusion of the experiment and histopathology was scored in panel B. Pathology is from one experiment with n = 9-10 per group. See text for details.
Figure 4
Figure 4
Fewer colon TS1 cells accumulate in recipients of TEM than in recipients of TN or TCM. HA104 mice received 750cGy and 8 × 106 RAG−/− BM cells in combination with 3000 TS1 TN, TCM, or TEM. On days 7, 14, 21, and 28, mice were killed and spleen, liver, BM, and colon cells were isolated. In addition, skin, colon, and liver samples were taken for analysis of histopathology. Representative FACS plots of CD4 and TS1 staining in the spleen, liver, BM and colon of TN, TCM, and TEM recipients 14 days after transplantation are shown in (A). Total numbers of TS1 in spleen, liver, BM and colons of TN, TCM and TEM recipients are shown in (B). In the colon, P values comparing the number of TS1 cells in TN versus TEM recipients were as follows: day 7, P = .0021; day 14, P = .0015; day 21, P < .0001; day 28, P = .0286. Skin, liver and colon pathology scores are shown in (C). For day 21 colon scores, P = .0025 comparing scores in recipients of TEM to the combined scores from TN and TCM recipients. Results shown are combined from 2 independent experiments. In the first experiment, a minimum of 4 mice per group were killed on days 7,14, 21, and 28. In the second experiment a minimum of 4 mice per group were killed on days 7, 14, and 21. Day 21 pathology scores for TN recipients are also shown in Figure 1D.
Figure 5
Figure 5
Progeny of TS1 TEM are outcompeted by progeny of TS1 TN. HA104 mice received 750cGy and 8 × 106 RAG−/− BM cells in combination with 3000 Thy1.1 TS1 TN, 3000 Thy1.2 TS1 TEM, or a mix of both. On days 14, 21, and 28 spleen and colon cells were isolated. Representative flow cytometry plots showing Thy1.1 and Thy1.2 expression on splenic CD4+TS1+ cells on day 14 are shown in (A). The numbers of TS1 cells in the spleen and colon are shown in (B). P < .05 comparing numbers of TEM that are transferred alone to numbers of TEM that are cotransferred with TN in the spleen and colon for all time points analyzed except for the colon on day 28, for which P = .138. Days 14 and 21 are combined from 2 independent experiments; day 28 is from 1 experiment. There were 8 mice per group for days 14 and 21 and 3 mice per group for day 28.
Figure 6
Figure 6
Fewer colon TS1 proliferate in TEM than in TN recipients. Mice were transplanted as in Figure 5. On days 14, 21, and 28, mice received BrdU 30 minutes before sacrifice. (A) Representative BrdU staining on CD4+TS1+ cells recovered from colon on day 14. The no BrdU control depicts a recipient of TS1 TN and TEM that was not injected with BrdU. Percentages of colon (B) and splenic (C) CD4+TS1+ cells that are BrdU+. For each time point, data were combined from 2 independent experiments with similar results.
Figure 7
Figure 7
Progeny of TS1 TEM produce less IFN-γ than progeny of TS1 TN. HA104 mice received 750cGy and 8 × 106 RAG−/− BM cells in combination with 3000 TS1 TN, TCM or TEM. (A) Expression of CD62L and CD44 for CD4+ TS1+ cells in the spleen on days 7, 14 and 21. (B-E) HA104 recipients were transplanted with 3000 TS1 TN or TEM as described in panel A. On day 21, spleen and colon cells were isolated, stimulated with PMA and ionomycin and stained for IFN-γ and IL-2. Representative FACS plots with and without stimulation are shown for the colon (B) and for the spleen (D). The percentages of TS1 cells that are IFN-γ+ or IL-2+ and the MFIs of the IFN-γ+ or IL-2+ cells are shown for the colon (C) and the spleen (E). Data are combined from 2 independent experiments (total of 8 mice per group).
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