Role of Ox40 Signals in Coordinating Cd4 T Cell Selection, Migration, and Cytokine Differentiation in T Helper (Th)1 and Th2 Cells

Our survival depends on our ability to clonally expand rare CD4 lymphocytes and instruct them to help effector cells. Two very different types of CD4 T cell response are required for protective immunity. Immunity to intracellular infections like tuberculosis is dependent on priming and expanding inflammatory IFN-␥ –expressing CD4 T cells that acquire the capability to migrate out into the tissue and activate macrophages to kill infected cells. In contrast, immunity to the exotoxin produced by diphtheria requires CD4 T cells to be primed to migrate into B follicles to foster germinal center (GC) development and the rapid production of high-affinity neutralizing antibodies. Although the outcomes of these two types of CD4 response are different , they have the same three components: (a) Identification and expansion of antigen-specific CD4 T cells; (b) instruction to secrete the appropriate cytokines; and (c) instruction to express chemokine and adhesion molecules that guide their migration to the appropriate location. Recent evidence has highlighted the fact that dendritic cells (DCs) direct CD4 T cell fate during priming (1), and this has focused attention on costimulatory interactions at the initiation of CD4 immune responses. In addition to their potential to costimulate CD4 cells through CD28 ligands and IL-12, DCs have recently been shown (2, 3) to express the ligand for the CD4 activation antigen, OX40. Both OX40 and its ligand are upregulated during CD4 T cell priming (4), and a model that illustrates the putative costimulatory events is shown in Fig. 1. Role of OX40 and CD28 in Priming CD4 Cells: Rapid Expansion in the T Zone. The CD28 ligand, CD86, is consti-tutively expressed on mature DCs, so all antigen-specific CD4 T cells receive an initial CD28 signal. In contrast, expression of the T cell activation antigen OX40 on naive CD4 T cells is largely CD28 dependent, both in vivo and in vitro (5). Although others have suggested that OX40 expression is CD28 independent (6), these studies looked at total rather than naive CD4 T cell responses. This is critical , as activated T cells appear to secrete cytokines that can both promote the survival of naive CD4 T cells and upreg-ulate OX40 (unpublished observations). After activation, CD4 T cells reciprocally activate DCs through CD40. In vitro, CD40 ligand (CD40L) upregulates the expression of IL-12 in cultured DCs (7), but this may not happen in vivo for the following reason: CD4-dependent recognition of foreign proteins presented …