Lymphotoxin β Receptor Controls T Cell Progenitor Entry to the Thymus

Abstract

The recruitment of lymphoid progenitors to the thymus is essential to sustain T cell production throughout life. Importantly, it also limits T lineage regeneration following bone marrow transplantation, and so contributes to the secondary immunodeficiency that is caused by delayed immune reconstitution. Despite this significance, the mechanisms that control thymus colonization are poorly understood. In this study, we show that in both the steady-state and after bone marrow transplant, lymphotoxin β receptor (LTβR) controls entry of T cell progenitors to the thymus. We show that this requirement maps to thymic stroma, further underlining the key importance of this TNFR superfamily member in regulation of thymic microenvironments. Importantly, analysis of the requirement for LTβR in relationship to known regulators of thymus seeding suggests that it acts independently of its regulation of thymus-homing chemokines. Rather, we show that LTβR differentially regulates intrathymic expression of adhesion molecules known to play a role in T cell progenitor entry to the thymus. Finally, Ab-mediated in vivo LTβR stimulation following bone marrow transplant enhances initial thymus recovery and boosts donor-derived T cell numbers, which correlates with increased adhesion molecule expression by thymic stroma. Collectively, we reveal a novel link between LTβR and thymic stromal cells in thymus colonization, and highlight its potential as an immunotherapeutic target to boost T cell reconstitution after transplantation.

Administration of RANKL boosts thymic regeneration upon bone marrow transplantation

“…Consistently, we found that LTα expression is required for the expression of adhesion molecules and chemokines, known to promote T‐cell progenitor entry in the thymus, in stromal cells during BMT. In accordance with our data, it has been recently reported that LTβR regulates at steady state thymus homing by controlling VCAM‐1 and ICAM‐1 on endothelial cells (Lucas et al , ; Shi et al , ). Peripheral T‐cell reconstitution is thus altered in BM‐transplanted LTα −/− mice, which is explained by a diminished thymic export of CD4 + and CD8 + T cells revealed by a weak frequency of recent thymic emigrants.…”

A key role for IL‐7R in the generation of microenvironments required for thymic dendritic cells

“…Furthermore, ETPs are severely depleted in the Rag2 −/− thymus ( 50 and unpublished observations), which also have disorganized thymic architecture, suggesting that their recruitment or maintenance is faulty without the proper microenvironmental conditions. ETPs are also depleted in the Ltbr −/− thymus 48 , further implicating this pathway in the defects in Il7r −/− thymic structure.…”

“…The mechanistic basis for a failure in thymic crosstalk between Il7r −/− thymocytes and TECs has yet to be determined, but previous studies suggest a role for IL-7R signaling in inducing the expression of TNF receptor and ligand family members that are involved in thymic crosstalk 44, 47 . One prime candidate is LTβR, since TECs from Ltbr −/− mice are deficient in their ability to make CCL19, but competent to make CCL21, CCL25, and CXCL12, reminiscent of the Il7r −/− TEC gene expression profile 48 .…”

“…44,47 One prime candidate is lymphotoxin beta receptor, as TECs from Ltbr −/− mice are deficient in their ability to make CCL19, but competent to make CCL21, CCL25 and CXCL12, reminiscent of the Il7r −/− TEC gene expression profile. 48 Another population that was clearly impacted by the absence of Il7r was ETPs. ETPs, which do not express easily detectable levels of Il7r, Figure 4 Perturbation in chemokine expression in the Il7r −/− thymus.…”

The natural history of naive T cells from birth to maturity

“…While these parameters were sufficient to explain the size of the DN compartment size and its output, the granularity of the description may confound influx and proliferation. Studies enumerating ETP in the adult thymus reveal around 1000 cells and others suggest that entry of precursors into the thymus may be episodic rather than a steady flow . A further level of complexity comes from studies suggesting that ETP also have self‐renewing capacity, revealed following thymus transplantation into IL7R‐deficient hosts that lack common lymphoid progenitors, and it is possible this capacity may serve to ensure steady thymic repopulation and output in the face of inconsistent progenitor input.…”