A model of Th2 differentiation based on polarizing cytokine repression

Current dogma holds that functional differentiation of helper T cells expressing lineage-specifying transcription factors and signature cytokines requires three signals provided by dendritic cells (DCs). T cell receptor (TCR) signaling (or signal 1) defines specificity, costimulation (or signal 2) ensures full T activation and expansion, and polarizing cytokines (or signal 3) upregulate specific master transcription factors thereby guiding T cell differentiation into distinct functional helper subsets. However, in vitro and in vivo studies provide evidence suggesting that Th2 cell differentiation may follow a particular DC–T cell two-signal activation model, in which signals 1 and 2 are required in the absence of signal 3. We propose a model that bypasses the need for signal 3, and instead, Th2 cell commitment requires the active suppression of polarizing cytokine secretion by DCs. Conventional dendritic cells (cDCs) can integrate multiple stimuli from the environment and provide three separate outputs in terms of antigen presentation, costimulation, and cytokine production; this guides the activation, expansion, and differentiation of distinct functional T helper subsets. Accordingly, the current dogma posits that T helper cell specification requires these three signals in sequence. Data show that T helper 2 (Th2) cell differentiation requires antigen presentation and costimulation from cDCs but does not require polarizing cytokines. In this opinion article, we propose that the ‘third signal’ driving Th2 cell responses is, in fact, the absence of polarizing cytokines; indeed, the secretion of the latter is actively suppressed in cDCs, concomitant with acquired pro-Th2 functions. Conventional dendritic cells (cDCs) can integrate multiple stimuli from the environment and provide three separate outputs in terms of antigen presentation, costimulation, and cytokine production; this guides the activation, expansion, and differentiation of distinct functional T helper subsets. Accordingly, the current dogma posits that T helper cell specification requires these three signals in sequence. Data show that T helper 2 (Th2) cell differentiation requires antigen presentation and costimulation from cDCs but does not require polarizing cytokines. In this opinion article, we propose that the ‘third signal’ driving Th2 cell responses is, in fact, the absence of polarizing cytokines; indeed, the secretion of the latter is actively suppressed in cDCs, concomitant with acquired pro-Th2 functions. receptor expressed on T cells that binds to CD80 (B7.1) and CD86 (B7.2) proteins expressed on activated dendritic cells and provides costimulatory signals necessary for T cell activation, proliferation, and survival. technology to map genome-wide locations of DNA-associated proteins such as transcription factors or modified histones. biological mechanism in B cells which allows the switch in immunoglobulin production from one isotype to another, such as from IgM to the IgG, IgE, or IgA isotypes. innate cells residing in peripheral tissues and secondary lymphoid organs whose primary function is to capture, process, and present protein-derived peptides to T cells and mediate their activation and functional polarization. activated CD4+ T cells that migrate to peripheral tissues where they secrete signature cytokines and activate local immune responses to eliminate the pathogens that caused their activation. type of innate lymphoid cells that produce type-2 cytokines, such as IL-13, and are involved in early responses against allergens and helminth infections. heterotrimeric protein comprised of α chain (IL-2Rα or CD25), β chain (IL-2Rβ or CD122), and γ chain (IL-2Rγ or common γ chain); binds IL-2 with high affinity on activated T cells and Treg cells. group of genes encoding proteins found on the surfaces of antigen-presenting cells, such as dendritic cells, whose primary function is to bind peptide fragments derived from proteins and display them on the cell surface for recognition by the appropriate CD4+ T cell. class of germline-encoded receptors that recognize molecules frequently found in pathogens (so-called pathogen-associated molecular patterns or PAMPs). Activation of PRRs results in the expression of a variety of polarizing and proinflammatory cytokines and the upregulation of costimulatory molecules; this is crucial for the initiation of innate immunity and a prerequisite for subsequent activation and shaping of adaptive immunity. technology used for the detection and quantitative analysis of mRNA molecules in a biological sample. technology used to examine RNA transcripts of individual cells, providing a high-resolution view of cell-to-cell variation. specialized subset of CD4+ T cells defined by the expression of the transcription factor Bcl6; they provide help to B cells and are essential for the germinal center formation, antibody isotype switching, affinity maturation, and the development of high-affinity antibodies and memory B cells. subset of Treg cells that suppress Tfh cells and B cells; characterized by co-expression of the transcription factors Bcl6 and Foxp3. type of PRR that initiate immune responses by sensing PAMPs. In mammals, a total of 13 TLRs (TLR1-13) have been found; however, humans express only 10 (TLR1-10) of them. Examples of PAMPs recognized by TLRs include bacterial cell surface lipopolysaccharides (LPS), lipoproteins, and peptidoglycans; proteins such as flagellin from bacterial flagellae; single- and double-stranded RNA of viruses; unmethylated CpG islands of bacterial and viral DNA. distinct from cDC1s; characterized by surface expression of CD11b and CD172α (SIRPα) and the requirement for the transcription factor IRF4 for their development from common DC progenitors.