Figure 8.

Schematic diagram and probable mechanism of arrest of DN2 pro-T cell-to-DN3 transition and promotion of its conversion to thymic dendritic cells by reciprocal regulation of Ikaros/Notch1 signaling: (A) During maturation, the T lymphocytes progress through the DN1, DN2a, DN2b, DN3a, DN3b, and DN4 to DP stages within the thymic cortex. These DP cells pass the cortico-medullary junction (CMJ) to enter the medulla as they further mature to SP (DN, Double negative; DP, Double positive; SP, Single positive). (B) Under the influence of tumor, thymus becomes atrophied, and Keratin-5 expressing IL-10-rich stromal cells tend to accumulate at the CMJ. (C) IL-10 molecules secreted from these cells interact with DN2b T cells via IL-10 receptors (IL-10R). (D) However, following IL-10–IL-10R interaction(s), STAT3-mediated intracellular signaling events occur within the DN2 T cells, which ultimately bring down Notch1 expression. As a consequence, the T cells are arrested at the DN2b stage. (E) Other than Notch1, downregulation of CCR7 and upregulation of Ikaros and IRF8 has also been observed due to these signaling events. A few of these arrested DN2b T cells somehow interact physically with the Keratin 5⁺ thymic stromal cells at the CMJ (C.a) and differentiate into dendritic cells (C.b, F) instead of staying at DN2b or progressing to DN3. The precise mode of the physical interaction(s) between the DN2b T cells and the Keratin-5⁺ stromal cells (C.a) is yet to be elucidated.