However, it is tempting to speculate that the phosphorylation state of S814 on Kif23 could itself behave as a determinant ofMBRs�� longevity. It will be interesting to establish the phosphorylation status of S814 of Kif23 on MBRs in other cell types containing different number of MBRs and to verify if altering this phosphorylation could modulate the MBRs per cell ratio. Alternatively, it could be worth monitoring pS814 to probe MBRs during differentiation or embryogenesis. The circulating T cell pool contains multiple antigen-experienced subsets bearing distinct tissue tropisms. The two best understood are those associated with skin and intestine. Together, these two populations comprise at least half of all blood-borne Agexperienced T cells. Each subset is responsible for immunological memory and immunosurveillance of its own target tissue. In both mice and humans, skin-homing cells Fexaramine express E-selectin ligand and chemokine receptor 4, while smallintestine- homing cells express integrin a4b7 and CCR9. Each of these molecules is required for normal homing of each cell type to its respective target organ. Currently available immunosuppressants tend to immunocompromise patients overall, leaving them susceptible to opportunistic infection within any given tissue. In contrast, a tissue-selective immunomodulatory agent might ameliorate lesions in the affected site without rendering immunologically healthy tissues vulnerable to infection. As such, the lymphocyte trafficking field has long held as its ����holy grail���� the notion that a systemically administered pharmaceutical might be designed to selectively attenuate localized autoimmune symptoms. There is precedent that blocking the function of homing molecules can affect inflammation quite dramatically. For example, natalizumab, a humanized monoclonal antibody against the a4 integrin chain, is FDA approved as an anti-inflammatory agent. However, the targeted integrin chain is a component of several distinct integrin heterodimers, and is not associated with selective lymphocyte trafficking to any specific tissue. Nonetheless, drugs intended to modulate selective homing of T cells to FIN 56 particular tissues have not been as uniformly successful as previously hoped. The disappointing outcome of this approach to date may be partially explained by the discovery that many tissue-selective homing mechanisms rely on competition among lymphocyte subsets for entry into tissue from the circulation. For example, normal T cells are 20-fold more likely to accumulate within inflamed skin than otherwise identical cells that lack CCR4. However, CCR42/2 T cells do gain access to skin when such competition is removed; CCR42/2 mice have relatively normal densities of T cells in both inflamed and resting skin. Thus, CCR4 is required for skin homing only in a physiologically competitive environment. Ablation of the CCR4 function alters the environment such that CCR4 is no longer needed for skin homing. Less efficient mechanisms may then take over in guiding lymphocytes into tissues.