Selective Thymus Settling Regulated by Cytokine and Chemokine Receptors

Abstract

To generate T cells throughout adult life, the thymus must import hemopoietic progenitors from the bone marrow via the blood. In this study, we establish that thymus settling is selective. Using nonirradiated recipient mice, we found that hemopoietic stem cells were excluded from the thymus, whereas downstream multipotent progenitors (MPP) and common lymphoid progenitors rapidly generated T cells following i.v. transfer. This cellular specificity correlated with the expression of the chemokine receptor CCR9 by a subset of MPP and common lymphoid progenitors but not hemopoietic stem cells. Furthermore, CCR9 expression was required for efficient thymus settling. Finally, we demonstrate that a prethymic signal through the cytokine receptor fms-like tyrosine kinase receptor-3 was required for the generation of CCR9-expressing early lymphoid progenitors, which were the most efficient progenitors of T cells within the MPP population. We conclude that fms-like tyrosine kinase receptor-3 signaling is required for the generation of T lineage-competent progenitors, which selectively express molecules, including CCR9, that allow them to settle within the thymus.

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

“…In mammals, there is a high redundancy with multiple molecules regulating entry of hematopoietic precursors into the thymus, including CCL19-CCL21/ CCR7, CCL25/CCR9, and P-selectin/PSGL-1. Consistent with this overlap, abrogation of any one of these receptor-ligand interactions only modestly affects thymus colonization [22][23][24][25][26][27]. However, elimination of two interactions (CCR7 together with CCR9) can dramatically reduce the entry of ETPs [28,29].…”

“…Other findings also strongly support continued translational studies for the development of IT -based HSC transplantation strategies including: (a) a significantly more rapid kinetics of T-cell reconstitution following IT as compared to IV administration of HSC and (b) long-term thymopoiesis by IT-injected precursors in nonconditioned recipients, even across histocompatibility barriers (Fig. 2) [23,41,57,[60][61][62]. It will therefore be important to determine the clinical settings in which an IT transplantation approach, potentially enhancing HSC differentiation to a T lineage fate, will improve short-as well as long-term patient outcome.…”

“…Once progenitor cells enter into the thymus, the thymic environment generally results in their acquisition of a short-lived T-cell precursor phenotype (as has been previously shown for common lymphocyte progenitors [23,48]). It was initially thought that thymic settling progenitors lost myeloid potential before acquiring either T or B potential but a few recent studies showed that some progenitors within the thymus had lost B potential while retaining myeloid potential [49][50][51].…”

“…In these experiments as well, BM precursors were not found to give rise to long-term thymopoiesis but it is important to note that in the vast majority of these studies, the thymus was perturbed by irradiation prior to transplantation [32-34, 38, 42, 55, 56]. Furthermore, even in the absence of irradiation, elegant experiments showed that intrathymically injected BM progenitors do not sustain long-term thymopoiesis in wild-type (WT) mice where there is a normal importation of precursors [23]. However, recent studies, performed by our group and others, have shown that in immunodeficient mice, under conditions where competitive BM progenitors and/or early thymocyte progenitors are restricted, long-term thymus-autonomous T-cell differentiation can occur [57][58][59].…”

Impaired Accumulation of Antigen-Specific CD8 Lymphocytes in Chemokine CCL25-Deficient Intestinal Epithelium and Lamina Propria

“…This is because a very important component of normal lymphocyte trafficking, i.e., competition (26) for limited microenvironmental niches between CCR9 ϩ and CCR9 Ϫ thymocyte populations, is missing in CCR9 Ϫ/Ϫ mice. In fact, CCR9 Ϫ/Ϫ BM cells are 10-to 15-fold less likely to develop into mature T cells when equal numbers of CCR9 ϩ/ϩ competitor BM cells are present (6,10,12).…”