New insights into T cell biology and T cell-directed therapy for autoimmunity, inflammation, and immunosuppression

Abstract

T cell-directed therapies have become mainstays in the management of various autoimmune diseases and organ transplantation. The understanding of T cell biology has expanded greatly since the development of most agents currently in use. Here we discuss important recent discoveries pertaining to T helper cell differentiation, lineage commitment, and function. Within this context, we examine existing T cell-directed therapies, including new agents being evaluated in clinical and preclinical studies. We also use recent findings to speculate on novel targets.

Fig 1. Naïve CD4⁺ T helper cell differentiation, expression of lineage defining transcription factors and effecter cytokines

Pathways to established lineages are represented with solid arrows; more controversial lineage pathways are represented with dashed arrows. Transcription factors are labeled in gray. Factors currently being therapeutically targeted for T cells (phase III & above) appear in bold with an asterisk. `Plasticity' and established pathways of interconversion between lineages have not been diagrammed for simplicity. Select abbreviations: FICZ(6-formylindolo[3,2-b]carbazole/endogenous aryl hydrocarbon receptor ligand); RA(all-trans retinoic acid); TCDD(2,3,7,8-tetrachlorodibenzo-p-dioxin/synthetic aryl hydrocarbon receptor ligand)

Fig 2. Therapeutic targets of T cells in autoimmunity and immunosuppresion

A CD4⁺ T cell is activated by an APC through TCR binding of MHC bound antigen. CD28 and CTLA-4 compete for binding with B7 family members to result in costimulation or anergy, respectively. Downstream TCR signaling pathways, adhesion molecules, trafficking and cytokine receptors are also diagrammed. Factors currently being therapeutically targeted for T cells (phase III & above) appear in bold with an asterisk. Listing of relevant signaling pathways and factors is not exhaustive.