The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

Abstract

Our previous in vivo studies show that both the amount of Ag and the number of available naive CD4 T cells affect the Th1/Th2 phenotype of the effector CD4 T cells generated. We examined how the number of OVA-specific CD4 TCR transgenic T cells affects the Th1/Th2 phenotype of anti-SRBC CD4 T cells generated in vivo upon immunization with different amounts of OVA-SRBC. Our observations show that a greater number of Ag-dependent CD4 T cell interactions are required to generate Th2 than Th1 cells. We established an in vitro system that recapitulates our main in vivo findings to more readily analyze the underlying mechanism. The in vitro generation of Th2 cells depends, as in vivo, upon both the number of responding CD4 T cells and the amount of Ag. We demonstrate, using agonostic/antagonistic Abs to various costimulatory molecules or their receptors, that the greater number of CD4 T cell interactions, required to generate Th2 over Th1 cells, does not involve CD40, OX40, or ICOS costimulation, but does involve B7/CD28 interactions. A comparison of the level of expression of B7 molecules by APC and CD4 T cells, under different conditions resulting in the substantial generation of Th1 and Th2 cells, leads us to propose that the critical CD28/B7 interactions, required to generate Th2 cells, may directly occur between CD4 T cells engaged with the same B cell acting as an APC.

Immune Class Regulation and Its Medical Significance Part II of a Report of a Workshop on Foundational Concepts of Immune Regulation

“…The pertinence of the threshold mechanism in BALB/c mice is supported by the fact that the partial depletion of CD4 T cells in BALB/c mice, around the time of challenge with a million parasites, results in a stable cell‐mediated, Th1 response and so resistance . Thus, the threshold mechanism appears not only to account for the importance of different variables on the Th1/Th2 phenotype of the immune response generated, but the interdependence of these variables , the two most important of which are the dose of antigen and the number of parasite‐specific CD4 T cells. A potential further such variable is discussed is the next section.…”

“…only few foreign epitopes) only having the potential to generate Th1, cell‐mediated responses . The dose of more foreign antigens, with lower doses favouring the generation of cell‐mediated, Th1 and higher doses favouring antibody, Th2 responses . The time after immunization at which the Th1/Th2 phenotype of the immune response is assessed. Most immune responses evolve from an exclusive or predominant Th1 mode to one having a significant and, with time, a larger Th2 component .…”

“…This prediction has been tested in a number of systems. . Of particular interest is the observation that reducing the number of CD4 T cells present in mice susceptible to Leishmania major modulates the antiparasite response from a Th2 to a Th1 mode and thus allows the mice to contain the parasite .…”

Transcription Factor KLF2 in Dendritic Cells Downregulates Th2 Programming via the HIF-1α/Jagged2/Notch Axis

“…The essential cytokine for polarizing Th2, IL-4, is not produced by DCs, although KLF2 regulates it in T cells ( 28 ). Accessory molecules, including CD80/86, ICOSL, OX40L, and Jagged, reinforce Th2 differentiation ( 12 , 29 – 31 ). With the exception of Jagged, they boost the proliferation of T cells ( 32 ).…”

The Differentiation of CD4+ T-Helper Cell Subsets in the Context of Helminth Parasite Infection

“…Several lines of experimental evidence suggest that low-avidity interactions between T-cells and antigen presenting cells (APC) favor the development of Th2 immune responses ( 27 ) (Figure 1 A). Recent work in support of this possibility includes studies of differential activation of T-cells using antigens of varying affinities or concentrations ( 28 , 29 ), different T-cell–APC ratios ( 30 ) and, more recently, the reduced APC-naïve T-cell contact time observed when T-cells are primed in vivo in conditions that favor type 2 rather than type 1 differentiation ( 31 ). This model of Th2 priming is strongly supported by many elegant studies in well-defined experimental systems, often using homogeneous T-cell populations expressing clonal T-cell receptor (TCR).…”