The Effects of TLR Activation on T-Cell Development and Differentiation

Figure 2

T-cell development and differentiation. It is believed that thymic lymphoid progenitor cells are derived from circulating hematopoietic stem cells originating from the bone marrow. The initial CD4/CD8 double-negative (DN) thymocytes migrate from the corticomedullary junction to the subcapsular region of the cortex and sequentially transform into DN1 (CD44⁺CD25⁻), DN2 (CD44⁺CD25⁺), DN3 (CD44⁻CD25⁺), DN4 (CD44⁻CD25⁻) and pre-DP cells, which weakly express CD4, CD8, CD25 and CD44. Then CD4/CD8 double-positive (DP) thymocytes under the influence of a guanine nucleotide exchange factor for Ras, Sos1 develop TCRαβ surface expression. cTECs present self-peptide-MHC complexes to TCRαβ to induce clonal deletion or thymocytes developing into CD4 or CD8 SP cell lineage. nTreg cell development possibly begins at the DP stage. Foxp3⁺ DP thymocytes with a functional IL-7 receptor and upregulated expression of Bcl-2 protect themselves from being negative selected. Foxp3⁺ DP thymocytes with CD103 expression are possible precursors of Foxp3⁺ CD8⁺ SP cells and finally differentiate into nTreg cells. SP cells move to the medulla through CCR7-mediated chemotaxis and interact with mTECs, which promiscuously express multifarious “tissue-specific” antigens. These antigens are taken up by DCs and cross-presented to developing thymocytes to induce negative selection establishing self-tolerance or nTreg lineage development. Circulating DCs bearing peripheral tissue antigens are also recruited intrathymically for cross-presentation. mTECs are also able to serve as APCs to induce nTreg lineage development and negative selection. Hassall’s corpuscles are required to support nascent nTreg cell development. Positively selected mature thymocytes migrate through perivascular space in the corticomedullary junction and medulla and become peripheral naive T lymphocytes. When infection occurs, APCs process antigen and present epitope in combination with MHC molecules to TCR on the T-cell membrane in the presence of co-stimulatory molecules and with the help of specific cytokines to induce T-cell differentiation. IL-12 and IFN-γ are essential for the induction of Th1 cell. IL-4 and IL-2 are required for naive CD4⁺ T-cell differentiation into IL-4-producing Th2 cells. TGF-β stimulates naive CD4⁺ T cell to differentiate into Th17 cells in the presence of IL-6 or induces iTreg cell in the presence of IL-2. Th17 cells can also be induced by an alternative pathway through the cooperation of TGF-β and IL-21 without the participation of IL-6. Tfh cells are induced with the help of IL-6 (mice) or IL-12 (human) to produce IL-21, which backfeeds to promote Tfh cell differentiation. As a major transcription factor, T-bet along with STAT4 and STAT1 is essential for Th1 cell differentiation. Activated Th1 cell can produce IFN-γ and IL-2 to help CD8⁺ effector T-cell functioning. GATA3 is the Th2 master regulator. STAT6 and STAT5 are essential in Th2 cell differentiation and expansion. STAT3 cooperates with STAT6 in promoting Th2 cell development. TCF-1 participates in GATA3 activation and promotes STAT6-independent IL-4-producing Th2 cell differentiation. Th2 cells secrete IL-4, IL-5 and IL-13 to boost antibody production in B cells against extracellular parasites. Production of IL-17 by Th17 cells is ROR-γt and ROR-α dependent. STAT3 is involved in Th17 cell differentiation, expansion and maintenance. Th17 cells participate in the immune response against extracellular bacteria by production of IL-17. Treg cell development is controlled by Foxp3 that is required for Treg lineage commitment, differentiation, expansion and function. STAT5 promotes Treg cell development by enhanced expression of Foxp3. Treg cells play a critical role in maintaining homeostasis and immune tolerance by suppression of effector cell in a cell-contact or cytokine-mediated pattern. Lineage commitment of Tfh cell is controlled by Bcl-6, while Blimp-1 plays an inhibitory effect on Tfh cell generation and function. STAT3 is necessary for Tfh cell development. Tfh cells interact with B cells in germinal center to induce generation of long-lived plasma cells and memory B cells. Naive CD8⁺ T cell primed by signals from TCR and co-stimulatory molecules differentiate into early effector cell expressing transcription factor T-bet and cytotoxic cytokines, for example, IFN-γ, TNF-α to acquire partial cytolytic abilities. The early effector cell further differentiates into late effector cell or memory cell, and this is determined by multiple factors such as the strength of IL-2R and the presence of IL-12, the presence of distinct amounts of intracellular components such as proteasome, T-bet, CD8 and IL-7Rα, or the potency of TCR signals. T-bet and Blimp-1 are responsible for IFN-γ expression and participate in the cytolytic gene expression, for example, Granyeme B, Perforin to induce short-lived effector CD8⁺ T cells. STAT5 plays a critical role in maintenance of phenotype of effector CD8⁺ T cells. Eomes and Bcl-6 expressions favor memory CD8⁺ T-cells differentiation. STAT5 activation also promotes memory CD8⁺ T-cell survival.