Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 198, Issue 10, Pages 1595-1608Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20030874
Keywords
thymocyte; antigen receptor; signal transduction; Ca++; mitogen-activated protein kinase
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Funding
- NCI NIH HHS [CA78773, R01 CA078773] Funding Source: Medline
- NHLBI NIH HHS [P01 HL059561, HL059561] Funding Source: Medline
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The Vav family of Rho guanine nucleotide exchange factors is thought to orchestrate signaling events downstream of lymphocyte antigen receptors. Elucidation of Vav function has been obscured thus far by the expression of three highly related family members. We generated mice lacking all Vav family proteins and show that Vav-null mice produce no functional T or B cells and completely fall to mount both T-dependent and T-independent humoral responses. Whereas T cell development is blocked at an early stage in the thymus, immature B lineage cells accumulate in the periphery but arrest at a late transitional stage. Mechanistically, we show that the Vav family is crucial for both TCR and B cell receptor (BCR)-induced Ca2+ signaling and, surprisingly, is only required for mitogen-activated protein kinase (MAPK) activation in developing and mature T cells but not in B cells. Thus, the abundance of immature B cells generated in Vav-null mice may be due to intact Ras/MAPK signaling in this lineage. Although the expression of Vav1 alone is sufficient for normal lymphocyte development, our data also reveal lineage-specific roles for Vav2 and Vav3, with the first demonstration that Vav3 plays a critical compensatory function in T cells. Together, we define an essential role for the entire Vav protein family in lymphocyte development and activation and establish the limits of functional redundancy both within this family and between Vav and other Rho-guanine nucleotide exchange factors.
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