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Schultz, Bruce T.,Teigler, Jeffrey E.,Pissani, F.,Oster, Alexander F.,Kranias, G.,Alter, G.,Marovich, M.,Eller, Michael A.,Dittmer, U.,Robb, Merlin L.,Kim, Jerome H.,Michael, Nelson L.,Bolton, D.,Stre Cell Press 2016 Immunity Vol.44 No.1
<P>A central effort in HIV vaccine development is to generate protective broadly neutralizing antibodies, a process dependent on T follicular helper (Tfh) cells. The feasibility of using peripheral blood counterparts of lymph node Tfh cells to assess the immune response and the influence of viral and vaccine antigens on their helper functions remain obscure. We assessed circulating HIV-specific IL-21(+) CD4(+) T cells and showed transcriptional and phenotypic similarities to lymphoid Tfh cells, and hence representing peripheral Tfh (pTfh) cells. pTfh cells were functionally active and B cell helper quality differed depending on antigen specificity. Furthermore, we found higher frequency of pTfh cells in peripheral blood mononuclear cell specimens from the ALVAC+AIDSVAX (RV144) HIV vaccine trial associated with protective antibody responses compared to the non-protective DNA+Ad5 vaccine trial. Together, we identify IL-21(+) CD4(+) T cells as pTfh cells, implicating them as key populations in the generation of vaccine-evoked antibody responses.</P>
Liu, Bin,Ho, Hsiang-Ting,Brunello, Lucia,Unudurthi, Sathya D.,Lou, Qing,Belevych, Andriy E.,Qian, Lan,Kim, Do Han,Cho, Chunghee,Janssen, Paul M. L.,Hund, Thomas J.,Knollmann, Bjorn C.,Kranias, Evangel Oxford University Press 2015 Cardiovascular research Vol.108 No.2
<P><B>Aims</B></P><P>Cardiac calsequestrin (CASQ2) and histidine-rich Ca-binding protein (HRC) are sarcoplasmic reticulum (SR) Ca-binding proteins that regulate SR Ca release in mammalian heart. Deletion of either CASQ2 or HRC results in relatively mild phenotypes characterized by preserved cardiac structure and function, although CASQ2 knockout (KO), or Cnull, shows increased arrhythmia burden under conditions of catecholaminergic stress. We hypothesized that given the apparent overlap of functions of CASQ2 and HRC, simultaneous ablation of both would deteriorate the cardiac phenotype compared with the single knockouts.</P><P><B>Methods and results</B></P><P>In contrast to this expectation, double knockout (DKO) mice lacking both CASQ2 and HRC exhibited normal cardiac ejection fraction and ultrastructure. Moreover, the predisposition to catecholamine-dependent arrhythmia that characterizes the Cnull phenotype was alleviated in the DKO mice. At the myocyte level, DKO mice displayed Ca transients of normal amplitude; additionally, the frequency of spontaneous Ca waves and sparks in the presence of isoproterenol were decreased markedly compared with Cnull. Furthermore, restitution of SR Ca release was slowed in DKO myocytes compared with Cnull cells.</P><P><B>Conclusion</B></P><P>Our results suggest that rather than being functionally redundant, CASQ2 and HRC modulate cardiac ryanodine receptor-mediated (RyR2) Ca release in an opposing manner. In particular, while CASQ2 stabilizes RyR2 rendering it refractory in the diastolic phase, HRC enhances RyR2 activity facilitating RyR2 recovery from refractoriness.</P>