Transgenic Drak2 Overexpression in Mice Leads to Increased T Cell Apoptosis and Compromised Memory T Cell Development

Drak2 is a death-associated protein family serine-threonine kinase. Its expression and roles in the immune system were investigated in this study. According to in situ hybridization, Drak2 expression was ubiquitous at the mid-gestation stage in embryos, followed by more focal expression in various organs in the perinatal period and adulthood, notably in the thymus, spleen, lymph nodes, cerebellum, suprachiasmatic nuclei, pituitary, olfactory lobes, adrenal medulla, stomach, skin, and testes. Drak2 transgenic (Tg) mice were generated using the human β-actin promoter. These Tg mice showed normal T cell versus B cell and CD4 versus CD8 populations in the spleen, but their spleen weight cellularity was lower in comparison with wild type mice. After TCR activation, the proliferation response in Drak2 Tg T cells was normal, although their interleukin (IL)-2 and IL-4 but not interferon-γ production was augmented. Activated Drak2 Tg T cells demonstrated significantly enhanced apoptosis in the presence of exogenous IL-2. At the molecular level, Drak2 Tg T cells manifested a lower increase of anti-apoptotic factors during activation; such a change probably rendered the cells vulnerable to subsequent IL-2 insults. The compromised apoptosis in Drak2 Tg T cells was associated with reduced numbers of T cells with the memory cell phenotype (CD62Llo) and repressed secondary T cell responses in delayed type hypersensitivity. Our study demonstrates that Drak2 expresses in the T cell compartment but is not T cell-specific; it plays critical roles in T cell apoptosis and memory T cell development. Drak2 is a death-associated protein family serine-threonine kinase. Its expression and roles in the immune system were investigated in this study. According to in situ hybridization, Drak2 expression was ubiquitous at the mid-gestation stage in embryos, followed by more focal expression in various organs in the perinatal period and adulthood, notably in the thymus, spleen, lymph nodes, cerebellum, suprachiasmatic nuclei, pituitary, olfactory lobes, adrenal medulla, stomach, skin, and testes. Drak2 transgenic (Tg) mice were generated using the human β-actin promoter. These Tg mice showed normal T cell versus B cell and CD4 versus CD8 populations in the spleen, but their spleen weight cellularity was lower in comparison with wild type mice. After TCR activation, the proliferation response in Drak2 Tg T cells was normal, although their interleukin (IL)-2 and IL-4 but not interferon-γ production was augmented. Activated Drak2 Tg T cells demonstrated significantly enhanced apoptosis in the presence of exogenous IL-2. At the molecular level, Drak2 Tg T cells manifested a lower increase of anti-apoptotic factors during activation; such a change probably rendered the cells vulnerable to subsequent IL-2 insults. The compromised apoptosis in Drak2 Tg T cells was associated with reduced numbers of T cells with the memory cell phenotype (CD62Llo) and repressed secondary T cell responses in delayed type hypersensitivity. Our study demonstrates that Drak2 expresses in the T cell compartment but is not T cell-specific; it plays critical roles in T cell apoptosis and memory T cell development. To elucidate the molecular mechanisms of T cell activation and differentiation, we conducted DNA microarray analysis employing the mouse 15,000 cDNA panel of the NIA, National Institutes of Health, to compare gene expression patterns of resting versus activated T cells (anti-CD3 and anti-CD28 stimulation for 24 h). Drak2 was one of the genes found to undergo significant changes after activation and was thus selected for further investigation. Drak2 is a serine/threonine kinase belonging to a family of death-associated protein (DAP) 3The abbreviations used are: DAP, death-associated protein; Tg, transgenic; IL, interleukin; E3, ubiquitin-protein isopeptide ligase; RT, reverse transcription; WT, wild type; ISH, in situ hybridization; FITC, fluorescein isothiocyanate; En, embryonic day n; DTH, delayed-type hypersensitivity; PE, phycoerytherin. kinases that consists of DAP (1Deiss L.P. Feinstein E. Berissi H. Cohen O. Kimchi A. Genes Dev. 1995; 9: 15-30Crossref PubMed Scopus (542) Google Scholar), DRP-1 (2Inbal B. Shani G. Cohen O. Kissil J.L. Kimchi A. Mol. Cell. Biol. 2000; 20: 1044-1054Crossref PubMed Scopus (139) Google Scholar), ZIP kinase (3Kawai T. Matsumoto M. Takeda K. Sanjo H. Akira S. Mol. Cell. Biol. 1998; 18: 1642-1651Crossref PubMed Scopus (205) Google Scholar), DAPK2 (4Kawai T. Nomura F. Hoshino K. Copeland N.G. Gilbert D.J. Jenkins N.A. Akira S. Oncogene. 1999; 18: 3471-3480Crossref PubMed Scopus (113) Google Scholar), Drak1, and Drak2 (5Sanjo H. Kawai T. Akira S. J. Biol. Chem. 1998; 273: 29066-29071Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). Drak1 and Drak2 share 67.1% identity in their kinase domain and 24.2% identity in their non-catalytic regions (5Sanjo H. Kawai T. Akira S. J. Biol. Chem. 1998; 273: 29066-29071Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). Drak2 also shares about 50% identity in the kinase domain with other members of the family (2Inbal B. Shani G. Cohen O. Kissil J.L. Kimchi A. Mol. Cell. Biol. 2000; 20: 1044-1054Crossref PubMed Scopus (139) Google Scholar). Although DAP, DRP-1, and DAPK2 have a calmodulin regulatory domain in their C terminus, ZIP, Drak1, and Drak2 do not (1Deiss L.P. Feinstein E. Berissi H. Cohen O. Kimchi A. Genes Dev. 1995; 9: 15-30Crossref PubMed Scopus (542) Google Scholar, 2Inbal B. Shani G. Cohen O. Kissil J.L. Kimchi A. Mol. Cell. Biol. 2000; 20: 1044-1054Crossref PubMed Scopus (139) Google Scholar, 3Kawai T. Matsumoto M. Takeda K. Sanjo H. Akira S. Mol. Cell. Biol. 1998; 18: 1642-1651Crossref PubMed Scopus (205) Google Scholar, 4Kawai T. Nomura F. Hoshino K. Copeland N.G. Gilbert D.J. Jenkins N.A. Akira S. Oncogene. 1999; 18: 3471-3480Crossref PubMed Scopus (113) Google Scholar, 5Sanjo H. Kawai T. Akira S. J. Biol. Chem. 1998; 273: 29066-29071Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). DAP, DAPK2, and DRP-1 are localized in the cytosol (1Deiss L.P. Feinstein E. Berissi H. Cohen O. Kimchi A. Genes Dev. 1995; 9: 15-30Crossref PubMed Scopus (542) Google Scholar, 2Inbal B. Shani G. Cohen O. Kissil J.L. Kimchi A. Mol. Cell. Biol. 2000; 20: 1044-1054Crossref PubMed Scopus (139) Google Scholar, 4Kawai T. Nomura F. Hoshino K. Copeland N.G. Gilbert D.J. Jenkins N.A. Akira S. Oncogene. 1999; 18: 3471-3480Crossref PubMed Scopus (113) Google Scholar), ZIP kinase and Drak1 resides mainly in the nuclei (3Kawai T. Matsumoto M. Takeda K. Sanjo H. Akira S. Mol. Cell. Biol. 1998; 18: 1642-1651Crossref PubMed Scopus (205) Google Scholar, 5Sanjo H. Kawai T. Akira S. J. Biol. Chem. 1998; 273: 29066-29071Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar), and Drak2 is found in both the cytosol and nuclei (5Sanjo H. Kawai T. Akira S. J. Biol. Chem. 1998; 273: 29066-29071Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 6Matsumoto M. Miyake Y. Nagita M. Inoue H. Shitakubo D. Takemoto K. Ohtsuka C. Murakami H. Nakamura N. Kanazawa H. J. Biochem. (Tokyo). 2001; 130: 217-225Crossref PubMed Scopus (44) Google Scholar), suggesting different mechanisms of action. When DAP family kinases are overexpressed in various cells, apoptosis ensues, either directly or after cytokine stimulation (1Deiss L.P. Feinstein E. Berissi H. Cohen O. Kimchi A. Genes Dev. 1995; 9: 15-30Crossref PubMed Scopus (542) Google Scholar, 2Inbal B. Shani G. Cohen O. Kissil J.L. Kimchi A. Mol. Cell. Biol. 2000; 20: 1044-1054Crossref PubMed Scopus (139) Google Scholar, 3Kawai T. Matsumoto M. Takeda K. Sanjo H. Akira S. Mol. Cell. Biol. 1998; 18: 1642-1651Crossref PubMed Scopus (205) Google Scholar, 4Kawai T. Nomura F. Hoshino K. Copeland N.G. Gilbert D.J. Jenkins N.A. Akira S. Oncogene. 1999; 18: 3471-3480Crossref PubMed Scopus (113) Google Scholar, 5Sanjo H. Kawai T. Akira S. J. Biol. Chem. 1998; 273: 29066-29071Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar), indicating their involvement in apoptosis. The mechanism of action and regulation of the prototype DAP family kinase, DAP, at the molecular level have been better studied. During apoptosis, DAP can associate with tumor necrosis factor α receptor and Fas-associated death domain, whereas in surviving cells, it binds to 14-3-3 (7Henshall D.C. Araki T. Schindler C.K. Shinoda S. Lan J.Q. Simon R.P. J. Neurochem. 2003; 86: 1260-1270Crossref PubMed Scopus (62) Google Scholar). It phosphorylates myosin light chain II in vivo and is necessary for serum-induced stress fiber formation (8Kuo J.C. Lin J.R. Staddon J.M. Hosoya H. Chen R.H. J. Cell Sci. 2003; 116: 4777-4790Crossref PubMed Scopus (70) Google Scholar); it also phosphorylates p19arf and suppresses fibroblast oncogenic transformation (9Raveh T. Droguett G. Horwitz M.S. DePinho R.A. Kimchi A. Nat. Cell Biol. 2001; 3: 1-7Crossref PubMed Scopus (320) Google Scholar). DAP is capable of autophosphorylation, which is inhibitory to its kinase activity (10Shani G. Henis-Korenblit S. Jona G. Gileadi O. Eisenstein M. Ziv T. Admon A. Kimchi A. EMBO J. 2001; 20: 1099-1113Crossref PubMed Scopus (63) Google Scholar). It also interacts with DAP-interacting protein-1, which is an E3 ubiquitin ligase and regulates the cellular level of DAP (11Jin Y. Blue E.K. Dixon S. Shao Z. Gallagher P.J. J. Biol. Chem. 2002; 277: 46980-46986Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Much less is known about the mechanisms of action of Drak2. It autophosphorylates and phosphorylates myosin light chains as an exogenous substrate (5Sanjo H. Kawai T. Akira S. J. Biol. Chem. 1998; 273: 29066-29071Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar), although its endogenous substrates have not been identified. Drak2 interacts with a calcineurin homologous protein (6Matsumoto M. Miyake Y. Nagita M. Inoue H. Shitakubo D. Takemoto K. Ohtsuka C. Murakami H. Nakamura N. Kanazawa H. J. Biochem. (Tokyo). 2001; 130: 217-225Crossref PubMed Scopus (44) Google Scholar), but the biological significance of this interaction is not clear. According to DNA microarray (12Su A.I. Cooke M.P. Ching K.A. Hakak Y. Walker J.R. Wiltshire T. Orth A.P. Vega R.G. Sapinoso L.M. Moqrich A. Patapoutian A. Hampton G.M. Schultz P.G. Hogenesch J.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4465-4470Crossref PubMed Scopus (1267) Google Scholar) and real time reverse transcription (RT)-PCR analysis (13McGargill M.A. Wen B.G. Walsh C.M. Hedrick S.M. Immunity. 2004; 21: 781-791Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar) of different tissues, Drak2 is considered exclusively expressed in the T cell compartment; yet such analyses are not precise, because these methods cannot reveal possible focal Drak2 expression in certain organs. The immune system of Drak2 null mutant mice was investigated recently by McGargill et al. (13McGargill M.A. Wen B.G. Walsh C.M. Hedrick S.M. Immunity. 2004; 21: 781-791Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). Unexpectedly, in vitro, Drak2-/- T cells have no apparent defect in activation-induced apoptosis, after stimulation with anti-CD3 and anti-CD28; this leads to a conclusion by the authors that Drak2 does not play significant roles in T cell apoptosis. Interestingly, Drak2-/- T cells have a lowered threshold to stimulation, compared with wild type (WT) T cells; the mechanism of such a phenomenon has not been explored. In this study, we mapped the Drak2 expression pattern during ontogeny and conducted a detailed in vitro and in vivo investigation of its functions in the immune system, using transgenic (Tg) mice with actin promoter-driven Drak2 expression. The novelty of our study is as follows. We corrected two misconceptions that Drak is expressed only in the T cell compartment and that it does not involve T cell apoptosis. We also provided evidence that Drak2 controlled T cell memory response. In Situ Hybridization (ISH)—A 1516-bp ApaI/KpnI mouse Drak2 cDNA fragment (positions 1150-2676) derived was in and was which was to and using and for both and M. J. 2002; PubMed Scopus Google Scholar). were in and at was as M. J. 2002; PubMed Scopus Google Scholar). was conducted with was with followed by The were and with Drak2 cDNA fragment NIA, National Institutes of mouse cDNA to the in was with a was cells with was in and to The were with and the were by a of and were of of Drak2 Tg Drak2 cDNA was the with and and and in the human β-actin and β-actin The was The fragment the β-actin Drak2 and β-actin was and of the Tg mice was by DNA of the was with and by The DNA was after to the was by the Drak2 as was in the was conducted for subsequent The and were and to a The were for for one for for and for for and for for one in Tg and cells was by real time the and were and was with the for for one and for for and for for time was also conducted to and The and for were and for the of a the and for were and for the of a and the and for were and for the of a The was the as that used for Drak2 β-actin were as the and were and with the as for Drak2 time was in and the of and the expression of these Tg and lymph cells were by with the cells were with and with The were with followed by a possible of to and of as The cells were a with at and at for and with at and at for The cell is in and Drak2 is in B CD4 and CD8 cell populations in the spleen were by and expression in T cells was investigated by cells, as in our H. G. J. J. J. 2004; PubMed Scopus Google Scholar). was conducted in T cells or cells, to a H. Y. J. J. 2001; PubMed Scopus (63) Google Scholar). T cell and cells were to methods H. G. J. J. J. 2004; PubMed Scopus Google Scholar). were with or anti-CD3 In spleen cells were with spleen cells in Cell were and for and IL-4 by of T cells and cells was with of these methods have been detailed in our H. G. J. J. J. 2004; PubMed Scopus Google Scholar). of cells J. J. C. J. Google Scholar) were with using to the which the Drak2 as a after cells were by and with of about were and with to cell apoptosis. The cells were also selected with for a of cells the and were for in the presence of and for the of were by their with day was and the were by was after 24 day and were has been H. G. J. J. J. 2004; PubMed Scopus Google Scholar). To the secondary these mice were with the day day was and were by was after 24 day and were Drak2 during and expression during ontogeny is not Its expression was with DNA microarray and with real time in various (12Su A.I. Cooke M.P. Ching K.A. Hakak Y. Walker J.R. Wiltshire T. Orth A.P. Vega R.G. Sapinoso L.M. Moqrich A. Patapoutian A. Hampton G.M. Schultz P.G. Hogenesch J.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4465-4470Crossref PubMed Scopus (1267) Google Scholar, M.A. Wen B.G. Walsh C.M. Hedrick S.M. Immunity. 2004; 21: 781-791Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). The of these methods is that are not to focal expression in a We to the Drak2 expression pattern during embryonic day and in using an derived mainly the Drak2 which does not share significant with other members of the DAP kinase In the mid-gestation stage and Drak2 ubiquitous expression in organs and During the perinatal period and day Drak2 expression in organs but was in the C and expression after day as as in Drak2 was expressed in such as the thymus, spleen, and lymph in level were in the cerebellum, skin, and which probably the of organs that in the thymus, Drak2 were in the whereas in the spleen, in the In the and olfactory cerebellum, and and level expression. the suprachiasmatic nuclei were for Drak2 suggesting the involvement of Drak2 in the Drak2 was also expressed in the adrenal and regions of the and cells, and cells These that Drak2 expression is not to the T cells and its expression in no apoptosis that it has functions other the regulation of expression in selected in situ of selected for Drak2 expression. Hybridization with the various and and is as spleen olfactory IL, suprachiasmatic nuclei and adrenal cells; cells; and are and are with analysis of Drak2 expression. and spleen T cells were activated by anti-CD3 The of activation is of and are to Drak2 expression during T cell activation was investigated by and spleen T cells were with anti-CD3 and were at and 24 in two of Drak2 the were in cells; their after and 24 indicating after T cell of Drak2 Tg mice human β-actin promoter-driven Drak2 were generated to study Drak2 in vivo in the immune The for Tg mice is in Tg were by which to Tg mice and were in Drak2 expression in spleen T cells was by real time in Tg mice were not Drak2 protein in Tg and lymph T cells were by employing and Drak2 in nuclei and cytosol of Tg T cells to cell of in was compared with T cells, in which Drak2 were not the cells not and were for detailed study. These mice were and manifested no for their spleen a phenotype in vitro and in in of the for are and of Drak2 Tg T weight and cellularity were but reduced in Drak2 Tg mice. T versus B cell and CD4 versus CD8 cell in the spleen of Tg mice were with of of the T cell activation and was normal in Drak2 Tg T cells by anti-CD3 or We the cytokine production and proliferation of Tg T cells with T cells, IL-2 and IL-4 but not interferon-γ after anti-CD3 or anti-CD3 anti-CD28 stimulation in Tg T cells was the other the IL-2 and IL-4 Tg T cell proliferation by anti-CD3 or was with that of T cells, suggesting that IL-2 and IL-4 were not factors for in Activated Drak2 Tg T cells in the of of the DAP have been in apoptosis of various cell a that Drak2-/- T cells do not to undergo apoptosis after TCR (13McGargill M.A. Wen B.G. Walsh C.M. Hedrick S.M. Immunity. 2004; 21: 781-791Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). Drak2 Tg we to the of Drak2 T cell apoptosis not only after TCR but also the of which is critical for activated T cell apoptosis PubMed Scopus Google Scholar). and Drak2 spleen T cells were activated by anti-CD3 and anti-CD28; 24 exogenous IL-2 was at apoptosis was by in exogenous and Tg T cells of apoptosis versus In the presence of exogenous Tg T cells demonstrated a increase of apoptosis T cells versus TCR is known to T cell or TCR is probably a We the of and Tg T cells in the presence of IL-2 was different the TCR was To this and Tg T cells were to after stimulation with anti-CD3 and and IL-2 was as in the apoptosis was reduced in and Tg T cells compared with T cell as but Tg T cells a apoptosis T cells versus We in vitro Drak2 to our the of Drak2 in Tg T T cell J. J. C. J. Google Scholar) was with a Drak2 expression in which Drak2 cDNA was after a the of cells were after 24 with The cells were of in the with and the with After an cell apoptosis was with with cells with the cells with showed significantly apoptosis, as by We to cells using compared with cells with the cells a significantly proliferation to and only a of cells after a of about These cells to day after an of cells the and were with for and was to their in cells reduced because of their apoptosis Drak2 to cell apoptosis. It is to that in this cell IL-2 was and this was to that of in which enhanced apoptosis was in activated Tg T cells in the presence of IL-2. To the molecular mechanisms of T cell apoptosis associated with Drak2 we the expression of a of anti-apoptotic factors in Tg versus T and were expressed at in resting and Tg T cells and were significantly 24 after activation in T cells such was compromised in Tg T In the 24 24 to after the of in the presence or of the and Tg T cells was not apparent in of and although Tg T cells apoptosis in the presence of IL-2 at The that the compromised of these anti-apoptotic factors in activated Tg T cells at an stage 24 of activation rendered the T cells vulnerable to subsequent IL-2 insults. The of this that Drak2 regulates T cell such an is in the presence of IL-2 in T Cell in Drak2 Tg T cell in an immune apoptosis is in the of memory T cell PubMed Scopus Google Scholar). The apoptosis in activated Drak2 Tg T cells in the presence of exogenous IL-2 the that memory T cell in these mice in Tg mice T cells with one of the memory T cell were in compared with mice whereas such a phenotype was not apparent in Tg mice not T DTH, we memory T cell in Drak2 Tg mice. In the response after the Drak2 Tg and mice Tg mice significantly reduced secondary responses These that memory of the T immune response is in Drak2 Tg mice. In this study, we investigated the of Drak2 in T cell apoptosis and memory T cell development. are We have corrected a that Drak2 expression is T using DNA microarray and to Drak2 expression the T cell compartment (12Su A.I. Cooke M.P. Ching K.A. Hakak Y. Walker J.R. Wiltshire T. Orth A.P. Vega R.G. Sapinoso L.M. Moqrich A. Patapoutian A. Hampton G.M. Schultz P.G. Hogenesch J.B. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4465-4470Crossref PubMed Scopus (1267) Google Scholar, M.A. Wen B.G. Walsh C.M. Hedrick S.M. Immunity. 2004; 21: 781-791Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). The of methods is that not localized gene expression in Drak2 expression during embryonic was not ISH, we found that Drak2 was expressed during the mid-gestation and indicating the of this gene in embryonic development. Drak2-/- mice no in their (13McGargill M.A. Wen B.G. Walsh C.M. Hedrick S.M. Immunity. 2004; 21: 781-791Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar), but this have been to the and functions of other DAP family in Drak2 expression more with in the thymus, spleen, and lymph other regions and such as the olfactory nuclei in the the and regions in the stomach, the adrenal medulla, skin, and also showed Drak2 suggesting its functions the immune Drak2 expression in the system that this has roles not to apoptosis, which do not significantly in a normal Drak2 expression in the nuclei is because this is in the J. PubMed Scopus Google Scholar); Drak2 is one of a of genes with expression in the We the Tg mouse in light to their activity 1998; PubMed Scopus Google Scholar), but were not found compared with mice. It to Drak2-/- mice have an The Drak2 gene expression pattern by in situ a for further of Drak2 functions in different organs. promoter-driven Drak2 Tg mice were generated for such in this our was the of Drak2 in T to a of Drak2 in T cell apoptosis (13McGargill M.A. Wen B.G. Walsh C.M. Hedrick S.M. Immunity. 2004; 21: 781-791Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, Wen B.G. G. C. C. Hedrick S.M. Walsh C.M. PubMed Scopus Google Scholar). We have that Drak2 a critical in T cell apoptosis, but such an was only in the presence of exogenous IL-2. IL-2 is not only a critical for T cell activation, but it is also in activated T cell apoptosis, as by in PubMed Scopus Google Scholar). T cell apoptosis in after during an immune and in vivo IL-2 in the of activated T cells either as an or the of such apoptosis the of surviving T cells, which further memory T one of the for the in mice in IL-2 production gene null or IL-2 receptor gene null B. H. H. A. Cell. Full Text PDF PubMed Scopus Google Scholar, H. C. A. E. T. H. T. C. 1995; PubMed Scopus Google Scholar). we have found that secondary but not T cell responses were in Drak2 Tg and Drak2 Tg mice of these are with the that Drak2 memory T cell which was compromised in the presence of Drak2 It is that Drak2 expression was 24 after T cell activation after a Wen B.G. G. C. C. Hedrick S.M. Walsh C.M. PubMed Scopus Google Scholar). Although the of the is not the after 24 probably a mechanism to apoptosis of activated T cells by their threshold of IL-2 and of the activated T cells to and memory our that Drak2 is in memory T cell development. Drak2 apoptosis is not We that Drak2 Tg T cells in of anti-apoptotic such as and 24 after activation, although at that time Tg, and T cells no in their that Drak2 T cells to apoptosis by their by anti-apoptotic to elucidate the Drak2 and factor expression. In Drak2 Tg was a but of spleen weight and cellularity that compromised secondary immune responses to T cell apoptosis to such an this also B cells apoptosis is investigation. In our study that Drak2 plays critical roles in T cell apoptosis and memory T cell and this also has functions and to apoptosis in a of organs. of its mechanisms in T cell apoptosis is to anti-apoptotic which the cells vulnerable to insults. We for for in situ and the of the of for DNA microarray

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