Publications

Prior studies in CD4-deficient mice established the capacity of T helper (Th) lineage cells to mature into Th1 cells. Unexpectedly, challenge of these mice with Nippostrongylus brasiliensis, a Th2-inducing stimulus, failed to result in the development of Th2 cells. Additional studies were performed using CD4+ or CD4-CD8- (double-negative) T cell receptor (TCR) transgenic T cells reactive to LACK antigen of Leishmania major. Double-negative T cells were unable to develop into Th2 cells in vivo, and, unlike CD4+ T cells, could not be primed for interleukin-4 production in vitro. Similarly, CD4+ TCR transgenic T cells primed on antigen-presenting cells expressing mutant MHC class II molecules unable to bind CD4 did not differentiate into Th2 cells. These data suggest that interactions between the TCR, MHC II-peptide complex and CD4 may be involved in Th2 development.

BALB/c mice develop aberrant T helper 2 (Th2) responses and suffer progressive disease after infection with Leishmania major. These outcomes depend on the production of interleukin-4 (IL-4) early after infection. Here we demonstrate that the burst of IL-4 mRNA, peaking in draining lymph nodes of BALB/c mice 16 hr after infection, occurs within CD4+ T cells that express V beta 4 V alpha 8 T cell receptors. In contrast to control and V beta 6-deficient BALB/c mice, V beta 4-deficient BALB/c mice were resistant to infection, demonstrating the role of these cells in Th2 development. The early IL-4 response was absent in these mice, and T helper 1 responses occurred following infection. Recombinant LACK antigen from L. major induced comparable IL-4 production in V beta 4 V alpha 8 CD4+ cells. Thus, the IL-4 required for Th2 development and susceptibility to L. major is produced by a restricted population of V beta 4 V alpha 8 CD4+ T cells after cognate interaction with a single antigen from this complex organism.

The members of the matrix metalloproteinase gene family play critical roles in numerous physiologic events, including cellular migration, tissue remodeling in wound healing and development, as well as in the evolution of the inflammatory process. The 72 kDa gelatinase A (formerly denoted 72 kDa Type IV collagenase) is centrally involved in the inflammatory and sclerotic events common to most forms of chronic glomerular disease. In this article recent studies are summarized which demonstrate that this particular enzyme can directly affect the proliferative and differentiation properties of the intrinsic glomerular mesangial cell, both in vitro and in vivo.