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Abstract
RhoH, an atypical small Rho-family GTPase, critically regulates thymocyte differentiation through the coordinated interaction with Lck and Zap70. Therefore, RhoH deficiency causes defective T cell development, leading to a paucity of mature T cells. Since there has been no gain-of-function study on RhoH before, we decided to take a transgenic approach to assess how the overexpression of RhoH affects the development of T cells. Although RhoH transgenic (RhoHtg) mice expressed three times more RhoH protein than wild-type mice, β-selection, positive, and negative selection in the thymus from RhoHtg mice were unaltered. However, transgenic introduction of RhoH into Rag2 deficient mice resulted in the generation of CD4+CD8+ (DP) thymocytes, indicating that overexpression of RhoH could bypass β-selection without TCRβ gene rearrangement. This was confirmed by the in vitro development of DP cells from Rag2-/-RhoHtg DN3 cells on TSt-4/Dll-1 stroma in an Lck dependent manner. Collectively, our results indicate that an excess amount of RhoH is able to initiate pre-TCR signaling in the absence of pre-TCR complexes.
Highlights
T cells develop in the thymus through a complex multistage process
We have investigated the function of RhoH by utilizing RhoH transgenic (RhoHtg) mice under the control of the CD2 promoter
Overexpression of RhoH in thymocytes did not interfere with T cell development significantly, we found that excess RhoH resulted in bypass of the β-selection checkpoint, allowing differentiation from DN to double positive (DP) without TCRβ recombination in vivo
Summary
T cells develop in the thymus through a complex multistage process. It is well known that two major checkpoints exist during T cell development in the thymus. The first checkpoint is βselection (or pre-TCR checkpoint) at the CD4-CD8-CD25hiCD44low (DN3) stage, and the other is repertoire selection (positive and negative selection) at the CD4+CD8+ double positive (DP) stage. Progression through both stages is dependent on pre-TCR or TCR complexes, many TCR signal-related molecules are involved in these checkpoints [1, 2]. RhoH belongs to the Rho family small GTPases, which play crucial roles in the development of thymocytes [3]. Because RhoH is anchored to the plasma membrane through myristoylation, it is able to recruit Lck, ZAP70, and Syk to the membrane to facilitate membrane proximal signal transduction [6, 7, 9]
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