Commentary Vav‐1 and T cells

Abstract

[I 23942]Vav-1 is a protein expressed predominantly in hematopoietic cells. There has been much work on the biochemistry and biology of this protein and finally some clarity as to the role of Vav-1 in immune cells has been achieved. An excellent paper on this topic was recently published by Ardouin et al. [1].The involvement of Vav-1 in lymphocyte transduction was first indicated by biochemistry -it was seen that this protein was tyrosine-phosphorylated in response to antigen-receptor ligation. Vav-1 is also tyrosinephosphorylated, following ligation of the costimulatory molecule CD28, and forms protein complexes with the tyrosine kinase ZAP-70 and the adapter SLP-76 in activated T cells [2]. These are probably important in regulating Vav-1 cellular localization and catalytic activity. Initially, the predicted protein sequence of Vav-1 indicated that this protein was likely to be a transcription factor and hence its tyrosine phosphorylation was heralded as a mechanism to link antigen-receptors to the cell nucleus [3]. This view changed when a revised, correct Vav-1 sequence was published which revealed that Vav-1 is a 95-kDa protein with src-homology (SH) 2 and SH3 domains and a Dbl homology region which is a characteristic marker of guanine nucleotide exchange proteins (GEF) for Rho family GTPases [4]. There was then a brief period when it was suggested that Vav-1 was a GEF for Ras. However, now it is accepted that Vav-1 is not directly involved in Ras regulation but rather targets the Rho family GTPases Rac-1 and Rac-2 [5, 6].If the early predictions of Vav-1 function were confusing, analysis of Vav-1 knockouts then clarified the importance of this protein for lymphocyte biology. Hence, deletion of the Vav-1 gene by homologous recombination resulted in mice with both B and T cell defects [7]. Notably, mice lacking Vav-1 show severe defects in thymocyte development.In early thymocyte progenitors the process of TCR gselection occurs: cells that successfully rearrange their TCR g -locus and express a functional pre-TCR complex proliferate rapidly and undergo further differentiation to express the coreceptors CD4 and CD8. These cells then undergo TCR § -chain rearrangements and upon expression of a mature § g TCR complex are subjected to the processes of positive and negative selection which generate CD4 or CD8 single-positive thymocytes that exit to the periphery. Loss of Vav-1 causes problems in the two key antigen-receptor checkpoints. There is a marked thymocyte hypocellularity in Vav-null mice that is associated with an incomplete differentiation block at the DN3/ pre-TCR checkpoint stage [8]. This block is leaky but the cells that survive do not develop normally; they show inefficient positive and negative selection [9]. These defects mean that Vav-1-null mice have very few mature peripheral T cells. Moreover, the severe defects in thymocyte development caused by loss of Vav-1 must raise the question of whether Vav-1-null mice have any normal peripheral T cells.In this context, peripheral T cells from Vav-1-...

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