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The Related Adaptors, Adaptor in Lymphocytes of Unknown Function X and Rlk/Itk-Binding Protein, Have Nonredundant Functions in Lymphocytes¹

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Adaptors play a critical role in regulating signaling pathways that control lymphocyte development and activation. Adaptor in lymphocytes of unknown function X (ALX) and Rlk/Itk-binding protein (RIBP) are adaptors related by structure and sequence, coexpressed in T cells. Mice deficient for each adaptor demonstrated that ALX and RIBP, respectively, negatively and positively regulate T cell activation in response to TCR/CD28 stimulation. However, these results did not preclude that they may function redundantly in other cell populations, or in response to other stimuli. Therefore, to understand the relationship between these related adaptors, ALX/RIBP-deficient mice were generated. We demonstrate that although ALX and RIBP are expressed throughout T cell development, T cell development occurs normally in these mice. Using the H-Y TCR transgenic model, positive and negative selection were found to proceed unimpeded in the absence of ALX and RIBP. We demonstrate that RIBP is also expressed in B cells; however, RIBP- and ALX/RIBP-deficient mice had normal B cell development, and responded equivalently to wild type in response to IgM, CD40, B cell-activating factor/B lymphocyte stimulator, CpG, and LPS. Interestingly, T cells deficient in both ALX and RIBP behaved similarly to those deficient in ALX alone during T cell activation in response to TCR/CD28, exhibiting increased IL-2 production, CD25 expression, and proliferation, thus showing that ALX deficiency masked the effect of RIBP deficiency. ALX/RIBP-deficient T cells did not have any alterations in either activation-induced cell death or Th1/2 polarization. Therefore, we did not find any functional redundancy or synergy during lymphocyte development, selection, activation, or survival in ALX/RIBP-deficient mice, demonstrating that these molecules function independently.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 AI054974 to V.S.S., and a University of Pennsylvania Research Foundation grant to V.S.S.

² Address correspondence and reprint requests to Dr. Virginia Smith Shapiro, 288 John Morgan Building, Department of Pathology and Laboratory Medicine, 3620 Hamilton Walk, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. E-mail address: shapirov{at}mail.med.upenn.edu

³ Abbreviations used in this paper: ALX, adaptor in lymphocytes of unknown function X; BLyS, B lymphocyte stimulator; ETP, early T lineage progenitor; LAB, linker for activated B cells; LAT, linker for activated T cells; QPCR, quantitative real-time PCR; RIBP, Rlk/Itk-binding protein; SEB, staphylococcal enterotoxin B; SH2, Src homology 2; SP, single positive; DN, double negative.