Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

Abstract

T cell–APC interactions are essential for the initiation of effector responses against foreign and self-antigens, but the role of these interactions in generating different populations of effector T cells in vivo remains unclear. Using a model of CD4+ T cell responses to a systemic self-antigen without adjuvants or infection, we demonstrate that activation of APCs augments Th17 responses much more than Th1 responses. Recognition of systemic Ag induces tolerance in self-reactive CD4+ T cells, but induction of CD40 signaling, even under tolerogenic conditions, results in a strong, Ag-specific IL-17 response without large numbers of IFN-γ–producing cells. Transfer of the same CD4+ T cells into lymphopenic recipients expressing the self-antigen results in uncontrolled production of IL-17, IFN-γ, and systemic inflammation. If the Ag-specific T cells lack CD40L, production of IL-17 but not IFN-γ is decreased, and the survival time of recipient mice is significantly increased. In addition, transient blockade of the initial MHC class II-dependent T cell–APC interaction results in a greater reduction of IL-17 than of IFN-γ production. These data suggest that Th17 differentiation is more sensitive to T cell interactions with APCs than is the Th1 response, and interrupting this interaction, specifically the CD40 pathway, may be key to controlling Th17-mediated autoimmunity.

CD40 C/T-1 and CTLA-4 A/G49 SNPs are associated with autoimmune thyroid diseases in the Chinese population

“…While, in a different aspect, the study on the Chinese population did not find these association in Taiwanese in 2008 [4]. Moreover, CD40 C/T -1 was not found to be associated with HT in Koreans [15] or in Japanese [16]. Our case-control study has shown an association of CD40 C/T -1 SNPs with AITD in the Chinese Han population, that C allele raises the risk of GD, but not HT.…”

“…A study found that the C allele increased the expression of CD40 protein by enhancing the gene translation efficiency [14]. Actually, CD40 over-expression has been found on dendritic cells in GD [15]. An evidence for involvement of multiple cell types in autoimmune disease has shown that CD40 is upregulated on human thyroid follicular cells in GD [16].…”

Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis

“…33 Although no relationship between CD40L-CD40 interaction and T H 17 polarization has been described in humans, this issue has been addressed recently in mice, with contradictory results. Katzman et al 28 X-HIGM, suggesting that in humans, CD40L-CD40 interaction is either not involved in the generation of T H 17 cells or other yet unknown mechanisms compensate for the absence of CD40L-CD40 interaction. In addition, we found normal phosphorylation of STAT3, a transcription factor essential for T H 17 cell differentiation, 19 in CD4 1 T cells in the cocultures of C albicans-pulsed mDCs with T cells from patients with X-HIGM (data not shown).…”

“…27,28 To address the possibility that a defect in the generation of T H 17 cells underlies the susceptibility of patients with X-HIGM to fungal pathogens, we quantified the percentage of T H 17 cells and the secretion of IL-17 in the coculture of patient DCs with autologous T cells. We detected a similar percentage of T H 17 cells between patients with X-HIGM and normal controls after activation of PBMCs with phorbol 12-myristate 13-acetate and ionomycin (Fig 3, A).…”

Immunological cell type characterization and Th1–Th17 cytokine production in a mouse model of Gaucher disease

“…Notably, the GC-mediated DC-T cell interaction in promoting the Th1 and Th17 responses in 9V/null mice may also relate to its efficiency in inducing the CD40L expression, as CD40-CD40L crosstalk is important to the Th1 and Th17 responses [30, 47–50]. These results support GC as promoting the engagement of CD40 through T cell CD40L; This is a critical step for T cells activation and up-regulation of Th1 and Th17 immune responses [30, 43, 51, 52]. IL-12 cytokine initiates Th1 responses, whereas IL-6 and IL23 lead to Th17 responses [53–57].…”