Differential Effects of IL-2 and IL-6 on the Development of Three Distinct Precursor T-Cell Populations in the Thymus

Journal of Immunology Research, Aug 2018

Three distinct T-cell precursors: bone marrow cells that express low levels of the Thy-1 antigen but no lineage markers (Thy-1-lo/BM); CD4-, CD8-, and CD3- thymocytes that express low levels of the Thy-1 antigen (Thy-1-lo/Thym); and CD4-, CD8-, and CD3- thymocytes that express high levels of the Thy-1 antigen and the IL-2 R α chain (Thy-1

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Differential Effects of IL-2 and IL-6 on the Development of Three Distinct Precursor T-Cell Populations in the Thymus

Differential Effects of IL-2 and IL-6 on the Development of Three Distinct Precursor T-Cell Populations in the Thymus NAOKO NAKANO HITOSHI KIKUTANI TADAMITSU KISHIMOTO Three distinct T-cell precursors: bone marrow cells that express low levels of the Thy-1 antigen but no lineage markers (Thy-l-lo/BM); CD4-, CD8-, and CD3- thymocytes that express low levels of the Thy-1 antigen (Thy-l-lo/Thym); and CD4-, CD8-, and CD3thymocytes that express high levels of the Thy-1 antigen and the IL-2 R cz chain (Thy-1 // IL2R /) were isolated by fluorescence-activated cell sorter (FACS). These three populations expanded with different kinetics in the thymus of irradiated recipient mice after intrathymic transfer. When a high dose of human recombinant IL-2 (r-IL-2) or human recombinant IL-6 (r-IL-6) was administered, r-IL-6 accelerated donor Thy-1 +/IL2R to differentiate, whereas r-IL-2 blocked normal differentiation and expansion of donor Thy-l-lo/Thym, but did not show any significant effect on donor Thy-1 //IL2R /. Neither r-IL-2 nor r-IL-6 worked directly on donor Thy-lalo/BM in this transfer system. IL-2; IL-6; T-cell progenitor; thymic development - has been reported to work as a T-cell growth factor (Le et al., 1988; Uttenhove et al., 1988) , and it is possible that IL-6 plays a role in thymocyte development. In an attempt to understand the differentiation process of precursor T cells, we took advantage of intrathymic injection (Goldschneider et al., 1986) , combining with the three-color fluorescence-activated cell sorter (FACS) to isolate distinct T-cell precursors and to chase the fate of only donor-derived thymocytes in the host thymus. Effects of IL-2 and IL-6 on the development of T cells were also studied in this experimental system by administration of a relatively large amount of human recombinant IL-2 (r-IL-2) or human recombinant IL-6 (r-IL-6) to recipient mice that had been injected with sorted precursor T cells. RESULTS Capacity of Expansion and the Stage of Development of Precursor T Cells On the basis of Thy-1 and IL-2-R expression, double-negative and CD3-negative C3H/HeN thymocytes were subfractionated into three populations, IL-2-R / and IL-2-R- thymocytes (Thy-l+/ IL2R / and Thy-I//IL2R -, respectively), both of which express high levels of the Thy-1 antigen, and thymocytes with low levels of the Thy-1 antigen (Thy-l-lo/Thym) (Nakano et al., 1987) . Bone marrow cells expressing low levels of the Thy-1 antigen (Thy-l-lo/BM), which have been demonstrated to give rise to T cells as well as all lineages of hematopoietic cells (Muller-Sieburg et al., 1986) , were also sorted from C3H/HeN bone marrow cells as another source of precursor T cells. Sorted precursor T-cell populations were intrathymically injected into sublethally irradiated AKR/J recipients and examined for their ability to reconstitute the recipient thymuses. T cells derived from injected precursor cells were chased by staining the Thy-l.2 antigen, which allows distinguishing T cells of donor origin from those of host AKR/J (Thy-l.1), and Fig. 1A shows kinetics of expansion of donor-derived T cells detected as Thy-l.2 /. When I xl06 Thy-I//IL2R were injected, cells detectable as Thy-l.2 / tapered off within a few days and did not expand in the thymuses of irradiated recipients. In the recipient thymuses injected with 2x10 Thy-I+/IL2R / cells, B a b Thy-llL2oot Thy-l-loKhymoot day 11 day 12 C Thy-l-lo/BM / 0 CD8 00 CD8 CD8 CD8 oo ;o ;oo CD8 day 18 day 38 Thy-l.2 / donor-derived cells expanded one I//IL2R +, Thy-l-lo/Thym, and Thy-l-lo/BM, all of hundredfold within 10-14 days and decreased there- which were capable to expand in the thymus, as after. T cells derived from this precursor population described before. First, irradiated AKR/J recipients were mostly CD4+/CD8 / on day 11, and gradually were intrathymically transferred with Thy-I//IL2R + shiftedtoward CD4 //CD8- and CD4-/CD8 / on day C3H/HeN cells and then injected with saline, 10 g 18, Fig. 1B(a). A delay in expansion of donor- of r-IL-2, or 10 g of r-lL-6 every day. By gating on derived thymocytes was observed when I xl0 Thy- donor-derived Thy-l.2 positive cells, the expression 1-1o/Thym was injected. Although cells detected as of CD4 and CD8 on the donor-derived thymocytes Thy-l.2 / expressed mostly both CD4 and CD8 on was analyzed on day 11. As shown in Fig. 2A, day 12, their cell number was only tenfold higher surface phenotypes of donor-derived cells were than that of injected cells, Fig. 1A and Fig. 1B(b). mostly CD4+/CD8 / at this point. The relative proThey continued to expand and reached the portion of CD4-/CD8-cells in r-IL-6-treated mice maximum level on day 21 with one hundredfold was lower than in the control, Fig. 2A(c). The absoexpansion. As shown in Fig. 1B(b), the differentiated lute number of donor-derived cells in r-IL-6-treated cells such as single positive cells were observed on recipient thymus was found to be several times day 21. The (...truncated)


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Naoko Nakano, Hitoshi Kikutani, Tadamitsu Kishimoto. Differential Effects of IL-2 and IL-6 on the Development of Three Distinct Precursor T-Cell Populations in the Thymus, Journal of Immunology Research, 1, DOI: 10.1155/1990/63249