DNA graphic

Joseph Craft, PhD


Yale University

Internal Medicine and Immunobiology


Characterization and function of CD4 T cell subsets in lupus

Pathogenic CD4 T helper (Th) cells are critical for disease promotion in systemic lupus erythematosus. These cells exert their effector function via autoreactive B cell help in secondary lymphoid organs (SLOs), including the spleen or lymph nodes, or by infiltration of tissues, such as the kidney. In both cases, autoantibody production and Th-cell infiltration, activation of innate immune cells ensues, mediated by autoantibody-autoantigen complex engagement and by tissue delivery of contact-dependent and soluble factors. The consequent inflammation leads to organ dysfunction and, sometimes, its loss. Thus, dissecting signals that promote CD4+ Th-cell differentiation and maintenance in lupus is critical for understanding pathways of disease initiation and progression, and for identification of new therapeutic targets, or confirmation of existing ones. CD4 Th-cell differentiation is initiated in SLOs after naïve T cells receive antigen (Ag) plus costimulatory signals delivered by dendritic cells (DCs), along with environmental cues including cytokines. The latter, acting via transcription factor induction and regulation, direct differentiation and maintenance of the classical Th-cell subsets, Th1, Th2, Th17, and follicular helper (Tfh) cells, among others. Th1, Th2, and Th17 cells drive inflammation in lupus via migration to and effector function in tissues, while Tfh cells remain in SLOs promoting autoreactive B cell maturation with generation of pathogenic memory B cells and long-lived autoantibody-producing plasma cells. Thus, tissue-effector Th subsets and SLO-resident Tfh cells contribute to tissue injury in SLE. The factors that promote Th1-cell, for example, and Tfh-cell differentiation in SLE, and as importantly, their maintenance and subsequent promotion of chronic tissue inflammation, are not clearly defined. We plan to do so in a lupus model, characterizing the steps required for pathogenic Th1- versus Tfh-cell differentiation and tissue maintenance and injury. While murine models of disease are excellent tools for studies of disease pathogenesis, their utility is magnified when their dissection is done in parallel with studies of SLE patients. We plan this combined approach. We will phenotypically and genetically characterize Th1 and Tfh cells in lupus, dissect the signals required for their development and maintenance, and determine their role in autoantibody formation and tissue injury, using novel cytokine reporter and gene-mutant mice. We will in parallel genetically characterize circulating Th1 and Tfh cells from patients with SLE, cells that in our preliminary studies have a phenotype similar to those we believe pathogenic in mice. Our aims are designed to meet a TIL goal to “characterize key steps in the pathogenesis of lupus that will allow for the development of new therapeutic agents”.


Together, ManyOne Can make a difference!