Entry of HIV-1 into target cells requires cell-surface CD4 and additional host cell cofactors. A cofactor required for infection with virus adapted for growth in transformed T-cell lines was recently identified and named fusin. However, fusin does not promote entry of macrophage-tropic viruses, which are believed to be the key pathogenic strains in vivo. The principal cofactor for entry mediated by the envelope glycoproteins of primary macrophage-tropic strains of HIV-1 is CC-CKR-5, a receptor for the beta-chemokines RANTES, MIP-1alpha and MIP-1beta.

Cytotoxic T lymphocytes (CTL) respond to antigenic peptides presented on MHC class I molecules. On most cells, these peptides are exclusively of endogenous, cytosolic origin. Bone marrow-derived antigen-presenting cells, however, harbor a unique pathway for MHC I presentation of exogenous antigens. This mechanism permits cross-presentation of pathogen-infected cells and the priming of CTL responses against intracellular microbial infections. Here, we report a novel diphtheria toxin-based system that allows the inducible, short-term ablation of dendritic cells (DC) in vivo. We show that in vivo DC are required to cross-prime CTL precursors. Our results thus define a unique in vivo role of DC, i.e., the sensitization of the immune system for cell-associated antigens. DC-depleted mice fail to mount CTL responses to infection with the intracellular bacterium Listeria monocytogenes and the rodent malaria parasite Plasmodium yoelii.

T helper 17 cells (T H -17 cells) are interleukin 17 (IL-17)-secreting CD4 + T cells involved in autoimmune disease and mucosal immunity. In naive CD4 + T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-β (TGF-β) and requires induction of the transcription factor RORγt. It has been suggested that human T H -17 cell differentiation is independent of TGF-β and thus differs fundamentally from mouse. We show here that a combination of TGF-β, IL-1β and IL-6, IL-21 or IL-23 in serum-free conditions was necessary and sufficient to induce IL-17 expression in naive human CD4 + T cells from cord blood. TGF-β upregulated RORγT expression but at the same time inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased IL-17 expression directed by RORγT, similar to what has been reported with mouse cells. Other gene products detected in T H -17 cells upon RORγT induction include CCR6, the IL-23 receptor (IL23R), IL17F and IL26. Together, these studies identify RORγT as having a central role in differentiation of human T H -17 cells from naive CD4 + T cells and suggest that similar cytokine pathways are involved in this process in mouse and human.T H -17 cells, the T helper cells that produce IL-17 and other pro-inflammatory cytokines, have been shown to have key functions in a wide variety of autoimmune disease models in mice and are thought to be similarly involved in human disease (reviewed 1-3). In healthy humans, IL-17-secreting cells are present in the CD45RO + CCR6 + populations of T cells from peripheral blood4,5 and gut5. T H -17 cells or their products have been associated with the pathology of multiple inflammatory or autoimmune disorders in humans. IL-17 protein and T H -17 CD4 + T cells are found in lesions from multiple sclerosis patients6-8 where they are thought to contribute to the disruption of the blood-brain barrier9. IL-17 is produced by CD4 + T cells of rheumatoid synovium10 and is thought to contribute to inflammation in rheumatoid arthritis11,12. In psoriasis, products associated with T H -17 cells, including IL-17, IL-17F, . IL-17 is induced in the gut mucosa from Crohn's disease and ulcerative colitis patients and T H -17 cells are detected13,16. IL-23, which is produced by dendritic cells in the intestine17, contributes significantly to T H -17 cell differentiation18. Strikingly, polymorphisms in the IL23R gene are associated with Crohn's disease, further implicating the T H -17 cell pathway in the pathogenesis19. HHMI Author Manuscript HHMI Author Manuscript HHMI Author ManuscriptThe mechanisms leading to differentiation of T H -17 cells have been well established in mice but they are still poorly understood in humans. In mice, differentiation of T H -17 cells that secrete IL-17 (also referred to as IL-17A) and IL-17F requires the expression of the transcription factors RORγt, an orphan nuclear hormone receptor, STAT3 and IRF4 (reviewed in reference 20). RORγt is sufficien...

Most developing thymocytes undergo apoptosis because they cannot interact productively with molecules encoded by the major histocompatibility complex. Here, we show that mice lacking the orphan nuclear hormone receptor RORgamma lose thymic expression of the anti-apoptotic factor Bcl-xL. RORgamma thus regulates the survival of CD4+8+ thymocytes and may control the temporal window during which thymocytes can undergo positive selection. RORgamma was also required for development of lymph nodes and Peyer's patches, but not splenic follicles. In its absence, there was loss of a population of CD3-CD4+CD45+ cells that normally express RORgamma and that are likely early progenitors of lymphoid organs. Hence, RORgamma has critical functions in T cell repertoire selection and lymphoid organogenesis.