This proposal will examine the role of CD5 as a regulator of T cell receptor (TCR) induced activation and its association with development and aging. CD5 a TCR associated molecule is expressed very early in T cell development with functions differentially in thymocytes and mature peripheral T cells. It appears to function as a negative regulator of TCR- dependent signaling in thymocytes whereas it potentiates activate via the TCR in mature T cells. Our data demonstrating the enhanced sensitivity of thymocytes from CD5 deficient mice to CD3 mediated deletion compared to wild type controls underscores the role of CD5 during T-cell development. We have now shown that a potential mechanism for this differential signaling is by the differential regulation of the serine/threonine kinase CK2. CK2 a critical kinase in regulating cell growth, differentiation via several signal transduction pathways, directly associates with CD5 and is regulated by the receptor. The regulation of CK2 by CD5 is dependent on the developmental stage and age of the T cell. The dogma had been that CK2 was involved only in distal signaling events, however, our data now clearly indicates otherwise. We propose that CD5-dependent regulation of CK2 is a major mechanism by which CD5 differentially regulates T cell biology with development and aging. We propose to define the in vivo role of CD-5 dependent regulation by reconstituting CD5 deficient mice with CD5 transgenes that lack the ability to activate CK2, thus generating essentially a signaling defective mouse. We will use this model to define changes in CD5-dependent signaling via CK2 regulation associated with aging and development. This approach will enable us to examine functions of molecules whose complete absence can be asked by compensatory changes during development.
The specific aims of the proposal are (1) To characterize the properties of CD5, and potential co-molecules, essential for CK2 activation, (2) Define the specific targets for CD5 dependent CK2 activation with regard to and (3) Establish the in vivo phenotype of CD5 deficient (-/-) mice and CD5 -/- reconstituted with altered CD5. We believe that this proposal will be important in understanding mechanisms that regulate T cell development and activation and pave the way to define aging associated changes in T cell signaling and break of tolerance. Novel therapeutic strategies can then be devised to target these pathways.
