Growth and Differentiation Advantages of CD4+OX40+ T Cells from Allogeneic Hematopoietic Stem Cell Transplantation Recipients Takero Shindo, Takayuki.

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Growth and Differentiation Advantages of CD4+OX40+ T Cells from Allogeneic Hematopoietic Stem Cell Transplantation Recipients Takero Shindo, Takayuki Ishikawa, Akiko Fukunaga, Toshiyuki Hori, Takashi Uchiyama Biology of Blood and Marrow Transplantation Volume 14, Issue 3, Pages 268-281 (March 2008) DOI: 10.1016/j.bbmt.2007.12.004 Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 The CD4+OX40+ T cell subset contains central memory T cells. (A-C) Peripheral blood CD4+ T cells of Allo HSCT recipients and HVs were analyzed for OX40, CD45RO, CCR7, and CD62L expression. (A) The frequencies of OX40-positive cells in the CD4+ T cell subset from 36 Allo HSCT recipients and 13 HVs are shown as means ± SD. ∗P < .01 (B) The dot plots shown are representative of 25 Allo HSCT recipients. (C) The frequencies of CD45RO-, CCR7-, and CD62L-positive cells in the OX40+ T cell subset from 4 Allo HSCT-recipients and 3 HVs are shown as means ± SD. (D) CD4+ T cells from Allo HSCT recipients and HVs were analyzed for correlations in their expression of CD25, OX40, intracellular Foxp3, and IL-7Rα. The dot plots shown are representative of 6 Allo HSCT recipients (upper) and 3 HVs (lower). Biology of Blood and Marrow Transplantation 2008 14, 268-281DOI: (10.1016/j.bbmt.2007.12.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 CD4+OX40+ T cells show an increased propensity to produce IL-2 in response to antigenic stimulation. (A) CD4+ T cells from Allo HSCT recipients and HVs were sorted into OX40+ and OX40− fractions. (B) Cytokine production by OX40+ and OX40− cells stimulated with αCD3/28. The data shown are representative of 10 Allo HSCT recipients (left) and 9 HVs (right). (C) The frequencies of cytokine-producing OX40+ and OX40− cells are shown as means ± SD. TIL-2 cells were defined as the cells that produce IL-2 but not IFN-γ or IL-4. ∗P < .01, #P < .05. Biology of Blood and Marrow Transplantation 2008 14, 268-281DOI: (10.1016/j.bbmt.2007.12.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 OX40+ memory T cells have greater survival and proliferation potentials. (A) CD4+ T cells from HVs were sorted into CD45RA−OX40+ T cells (OX40+ memory T cells) and CD45RA−OX40− T cells (OX40− memory T cells). Then, the cells were labeled with CFSE and cultured in the absence or presence of 1 ng/mL IL-7 for 5 days before measuring OX40 expression, division profile, and IL-2-production upon αCD3/28 stimulation. The dot plots shown are representative of 3 independent experiments. (B) CD4+ T cells of HVs were incubated for 15 minutes in the absence or presence of 1 ng/mL IL-7 and analyzed for OX40 and cytoplasmic phosphorylated-STAT5 (pSTAT5). Data are representative of 3 HVs. Biology of Blood and Marrow Transplantation 2008 14, 268-281DOI: (10.1016/j.bbmt.2007.12.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Crosslinking of OX40 enables OX40+ memory T cells to produce massive amounts of IL-2 for an extended time period. (A,B) CD4+ T cells from HVs were sorted into CD45RA−OX40+ T cells (OX40+ memory T cells) and CD45RA−OX40− T cells (OX40- memory T cells). (A) The cells were subjected to αCD3/28 or αCD3/28/OX40 stimulation for 24 hours. The levels of IL-2 secreted into the culture supernatants were measured by ELISA and are shown as means ± SD. (B) OX40+ memory T cells of HVs were stimulated with αCD3/28 or αCD3/28/OX40 and their IL-2-production 2-6 hours (upper) and 12-16 hours (lower) later was analyzed. The data shown are representative of 3 independent experiments. Biology of Blood and Marrow Transplantation 2008 14, 268-281DOI: (10.1016/j.bbmt.2007.12.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 The presence of OX40-mediated signaling during antigenic stimulation results in explosive cell growth. (A,B) OX40+ memory T cells and OX40− memory T cells from Allo HSCT recipients were labeled with CFSE, stimulated with αCD3/28 or αCD3/28/OX40 for 12 hours, washed, and cultured in growth medium for 4 days. (A) Upper dot plots show the PI-negative cells (viable cells) and lower histograms show the division profile of each cell population. The data shown are representative of 3 experiments. (B) The proportions of viable cells and proliferating cells are shown as means ± SD. ∗P < .01 #P < .02 (C) OX40+ memory T cells and OX40− memory T cells from HVs were labeled with CFSE, stimulated with αCD3/28 or αCD3/28/OX40 for 12 hours, washed, and then cultured in plates coated with mouse IgG1 (upper dot plots and histograms) or αOX40 Ab (lower dot plots and histograms) for 4 days. Dot plots show the PI staining and histograms show the division profile. The data shown are representative of 3 experiments. Biology of Blood and Marrow Transplantation 2008 14, 268-281DOI: (10.1016/j.bbmt.2007.12.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 CD4+OX40+ T cells from Allo HSCT recipients differentiate into Th1 or Th2 effector cells in response to αCD3/28/OX40 stimulation. CFSE-labeled OX40+ memory T cells and OX40− memory T cells from HVs (A) and Allo HSCT recipients (B) were stimulated with αCD3/28 or αCD3/28/OX40 for 12 hours, washed, cultured in medium for 4 days, and then restimulated with αCD3/28 for 6 hours. The division profile and cytokine production of the cells were then analyzed. (A) The dot plots are representative of 3 HVs. (B) The dot plots are representative of two Allo HSCT recipients. Biology of Blood and Marrow Transplantation 2008 14, 268-281DOI: (10.1016/j.bbmt.2007.12.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 7 Allo HSCT recipients with cGVHD have much higher frequencies of IL-2-producing CD4+OX40+ T cells than Allo HSCT recipients without cGVHD. Peripheral blood mononuclear cells from Allo HSCT recipients were stimulated with PMA/Iono stimulation for 4 hours in the continuous presence of BFA. (A) A representative dot plot of surface OX40 and intracellular IL-2 is shown. The gates were set at the CD4+ lymphocytes. (B) Comparison of the frequencies of OX40-expressing and IL-2-producing OX40+ cells in the CD4+ T cell populations of Allo HSCT recipients with (n = 15) and without (n = 10) cGVHD is shown. Biology of Blood and Marrow Transplantation 2008 14, 268-281DOI: (10.1016/j.bbmt.2007.12.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions