Programming memory T cell homing to target immunization strategies.

Targeting activated T lymphocytes to the site of pathogen invasion could greatly enhance the effectiveness of conventional vaccination protocols. We have devised a novel strategy to target the topographic distribution of memory T lymphocytes following vaccination. Specifically, we have observed that T cell priming in the presence of tissue-specific factors (particularly chemokines) favors the development of specific T cells with homing preference for the tissue, and therefore seek to fully establish the molecular mechanisms of this novel protocol of immunization and its potential application in clinical settings. Our preliminary studies and the forward experiments proposed will provide the opportunity for new therapeutic vaccination designs in the short-term. Besides its relevance to highly prevalent human gut infections (such as those induced by parasitic infection), this model will pave the way for the application of similar strategies to organ-selective targeting of T cell immunity in a range of diseases, including cancer.

The design of conventional immunization strategies has mainly focused on improving the magnitude and duration of memory T cell responses. Besides these important parameters, selective localization of primed T cells to sites of antigenic re-challenge is paramount for rapid and protective recall responses. Following priming, T cells acquire the ability to establish molecular interactions mediated by tissue-selective adhesion and chemokine receptors (homing receptors) that direct them to specific organs, thus allowing them to ?remember? the site where pathogen invasion has originally occurred. Thus, imprinting T cells with an ?area code? of the site where pathogen invasion is likely to re-occur will greatly enhance the development of rapid, protective immunity. We have recently designed a novel immunization protocol in which T cell activation in the presence of gut-derived chemotactic factors (CCL25) favors the development of memory T cells that express gut-homing receptors and selectively localize to gut-asssociated lymphoid tissue and gut tissue when adoptively transferred in vivo. We propose to fully investigate this novel protocol of immunization with the aim to achieve topographic immunological memory leading to targeted, faster and more effective recall responses. Besides the potential in the control of gut infections, we provide evidence that tissue-selective immunization can be achieved in a variety of other tissues (including humans), and propose that this protocol can be applied in human organ-specific infectious diseases other than those affecting the gut.