Adult T cell leukemia (ATL) is an aggressive neoplastic disease, in which a quarter of the patients develop opportunistic infections due to cellular immunodeficiency. However, the underlying mechanism responsible for the immunosuppression has remained unclear. Recent studies have demonstrated that the leukemia cells from a subset of patients with ATL express Foxp3, a specific marker for CD25+CD4+ regulatory T (Treg) cells, which regulate the immune response by suppressing CD4+ T cell functions. However, whether there is a functional resemblance between ATL cells that have Foxp3 expression and Treg cells is still unknown. In this report, we confirmed the high expression of Foxp3 in leukemia cells from 5 of 12 ATL patients and demonstrated that ATL cells from 3 patients suppressed the proliferation of CD4+ T cells. Similarly, one of six HTLV-I-infected cell lines showed both high Foxp3 expression and suppressive activity. Like Treg cells, the suppression induced by the ATL cells from two patients and the HTLV-infected cell line appeared to be mediated by a cell-cell contact-dependent mechanism. Nevertheless, among the ATL cells that strongly expressed Foxp3, those from two of the five patients showed no apparent suppressive activity. Furthermore, retroviral transfection of Foxp3 did not confer any suppressive function on low Foxp3-expressing HTLV-I-infected cell lines. These results indicate that Foxp3 may be essential but is not sufficient for the Treg-cell-like suppressive activity of ATL cells and HTLV-I-infected cell lines.
Signals through the OX40 costimulatory receptor on naive CD4 T cells are essential for full-fledged CD4 T cell activation and the generation of CD4 memory T cells. Because the ligand for OX40 is mainly expressed by APCs, including activated B cells, dendritic cells, and Langerhans cells, the OX40-OX40 ligand (OX40L) interaction has been thought to participate in T cell-APC interactions. Although several reports have revealed the expression of OX40L on T cells, the functional significance of its expression on them is still unclear. In this study, we demonstrate that Ag stimulation induced an increase in the surface expression and transcript levels of OX40L in CD4 T cells. Upon contact with OX40-expressing T cells, the cell surface expression of OX40L on CD4 T cells was markedly down-regulated, suggesting that OX40-OX40L binding occurs through a novel T cell-T cell interaction. To investigate the function of this phenomenon, we examined the proliferative response and survival of OX40L-deficient CD4 T cells when challenged with Ag. In vitro studies demonstrated markedly less CD3-induced proliferation of OX40L-deficient CD4 T cells compared with wild-type CD4 T cells. When using TCR transgenic CD4 T cells upon Ag stimulation, survival of OX40L-deficient T cells was impaired. Furthermore, we show that upon antigenic stimulation, fewer OX40L-deficient CD4 T cells than wild-type cells survived following transfer into wild-type and sublethally irradiated recipient mice. Taken together, our findings indicate that OX40L-expressing T cells have an autonomous machinery that provides OX40 signals through a T cell-T cell circuit, creating an additional mechanism for sustaining CD4 T cell longevity.
Memory T cells can be divided into effector memory (TEM) and central memory (TCM) subsets based on their effector function and homing characteristics. Although previous studies have demonstrated that TCR and cytokine signals mediate the generation of the two memory subsets of CD8+ T cells, the mechanisms for generation of the CD4+ TEM and TCM cell subsets are unknown. We found that OX40-deficient mice showed a marked reduction in the number of CD4+ TEM cells, whereas the number of CD4+ TCM cells was normal. Adoptive transfer experiments using Ag-specific CD4+ T cells revealed that OX40 signals during the priming phase were indispensable for the optimal generation of the CD4+ TEM, but not the CD4+ TCM population. In a different transfer experiment with in vitro established CD4+CD44highCD62Llow (TEM precursor) and CD4+CD44highCD62Lhigh (TCM precursor) subpopulations, OX40-KO TEM precursor cells could not survive in the recipient mice, whereas wild-type TEM precursor cells differentiated into both TEM and TCM cells. In contrast, TCM precursor cells mainly produced TCM cells regardless of OX40 signals, implying the dispensability of OX40 for generation of TCM cells. Nevertheless, survival of OX40-KO TEM cells was partially rescued in lymphopenic mice. During in vitro recall responses, the OX40-KO TEM cells that were generated in lymphopenic recipient mice showed impaired cytokine production, suggesting an essential role for OX40 not only on generation but also on effector function of CD4+ TEM cells. Collectively, the present results indicate differential requirements for OX40 signals on generation of CD4+ TEM and TCM cells.
We evaluated multiple patient characteristics for their prognostic significance in patients with peripheral T-cell lymphoma (angioimmunoblastic T-cell lymphoma [AITL; n = 31] and peripheral T-cell lymphoma, not otherwise unspecified [PTCL-NOS; n = 37]). Five-year overall survival (OS) rates in AITL and PTCL-NOS were 49% and 45%, respectively (p = 0.89). Cox proportional hazard model revealed that male sex, hemoglobin <10.0 g/dL and performance status (PS) > or =2 were independently associated with shorter OS in AITL. In patients with PTCL-NOS, low albumin, PS > or = 2, and mediastinal lymphadenopathy were independently associated with worse OS. When analysis in PTCL-NOS was performed incorporating Prognostic Index for PTCLu (PIT), low albumin and mediastinal lymphadenopathy were still both prognostic for OS. Three-year progression free survival (PFS) rates in AITL and PTCL-NOS were 49% and 47%, respectively (p = 0.578). None of the parameters was significantly associated with shorter PFS in AITL. In patients with PTCL-NOS, PS > or = 2 and mediastinal lymphadenopathy were independently associated with shorter PFS. The result is in keeping with previous large scale studies. Besides, we showed the potential prognostic importance of albumin and mediastinal lymphadenopathy in patients with PTCL-NOS.
T-cell homeostasis preserves the numbers, the diversity and functional competence of different T-cell subsets that are required for adaptive immunity. Naïve CD4 + T (T N ) cells are maintained in the periphery via the common γ-chain family cytokine IL-7 and weak antigenic signals. However, it is not clear how memory CD4 + T-cell subsets are maintained in the periphery and which factors are responsible for the maintenance. To examine the homeostatic mechanisms, CFSE-labeled CD4 + CD44 high CD62L low effector memory T (T EM ) cells were transferred into sublethally-irradiated syngeneic C57BL/6 mice, and the systemic cell proliferative responses, which can be divided distinctively into fast and slow proliferations, were assessed by CFSE dye dilution. We found that the fast homeostatic proliferation of T EM cells was strictly regulated by both antigen and OX40 costimulatory signals and that the slow proliferation was dependent on IL-7. The simultaneous blockade of both OX40 and IL-7 signaling completely inhibited the both fast and slow proliferation. The antigen-and OX40-dependent fast proliferation preferentially expanded IL-17-producing helper T cells (Th17 cells). Thus, OX40 and IL-7 play synergistic, but distinct roles in the homeostatic proliferation of CD4 + T EM cells.Keywords: Homeostatic proliferation r Memory CD4 + T cells r OX40 r Th17Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHomeostatic proliferation is a proliferative T-cell response induced by lymphopenia and helps control the size of the T-cell pool in the Correspondence: Prof. Naoto Ishii e-mail: ishiin@med.tohoku.ac.jp periphery [1,2]. This response not only contributes to the maintenance of T-cell homeostasis [1,2], but also to the pathogenesis of inflammatory diseases, including inflammatory bowel diseases (IBDs), graft versus host disease (GVHD), and type 1 diabetes * These authors contributed equally to this manuscript. Eur. J. Immunol. 2014. 44: 3015-3025 [ [3][4][5][6][7]. The homeostatic proliferation of naïve T (T N ) cells has been well studied by transferring T N cells into lymphopenic hosts, such as sublethally irradiated or Rag-deficient mice, and examining the division and differentiation of the donor cells in the spleen, lymph nodes, and gut tissues [8][9][10][11][12]. These studies demonstrated that the homeostatic proliferation of donor T N cells supplies a memoryphenotype T-cell pool [11,[13][14][15][16][17][18]. Notably, the T N cell populations undergoing homeostatic proliferation under lymphopenic conditions can be divided into two groups by their division rate: slow, in which the cells divide only one to three times per week, and fast, in which the cells divide more than seven times in a week [19]. The slow proliferation requires IL-7, occurs in secondary lymphoid organs, and produces a cell population that retains the naïve phenotype (CD44 low CD62L high ) and has limited differentiation potential [1,20,21]. In contrast, the fast proliferation...
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