Hypersensitivity-type granulomas (GR) are T cell-mediated chronic inflammatory lesions observed in a wide variety of infectious and noninfectious diseases often causing serious morbidity and mortality. Understanding the manner in which T cells participate and promote theses lesions will aid the development of interventions. These lesions can be classified as type-1 or type-2 based upon the relative participation of Th1 and Th2 associated cytokines. The current paradigm is that Th1 and Th2 CD4+ helper cells are recruited to inflammatory sites by chemokines (CK) and show selective migration by virtue of differential chemokine receptor expression. Using animal models of synchronized, type-1 and type-2 pulmonary GR formation elicited respectively by protein antigens of Mycobacteria tuberculosis and Schistosoma mansoni, we found indications of both shared and polarized CK receptor expression among type-1 and type-2 CD4+ memory helper cells as well as antigen stimulated regulation. However, the in vivo significance and contribution of these findings to GR formation is unknown. The present proposal will extend this work and test the hypothesis that effector Th1 and Th2 cells are recruited to inflammatory sites by way of innate phase chemokines through polarized post-activation chemokine receptors.
The specific aims will employ state-of-the-art laser capture microdissection (LCM) and real time, gene sequence detection technologies to reveal the microenvironmental expression and function of Th cell CK receptors.
Aim 1 will use LCM to define the temporal expression and tissue compartmental location of CK transcripts during synchronous Ag-bead and asychronous infectious type-1 and type-2 GR in order to allow correlation to T cell CK receptor expression.
Aim 2 will determine the distribution of induced CK receptor transcripts among effector Th1 and Th2 cells generated in vivo.
Aim 3 will reveal the potential biologic contribution Ag-induced receptors such as CXCR3, CCR4 and CCR8 to selective Th migration using direct chemotaxis of antigen-activated CD4+ T cells.
Aim 4 will define the temporal expression of CK receptor transcripts within the tissue microenvironments during synchronous Ag-bead and asychronous infectious type-1 and type-2 GR formation. Finally, Aim 5 will examine the migratory behavior of adoptively transferred CD4+ T cells with targeted CK receptor knockout and concomitant transgenic expression of green fluorescent protein (GFP). These studies will potentially provide novel and important information regarding the contribution of CK receptors to CD4+ T trafficking in chronic inflammatory responses. ? ? ? ?
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