[Show abstract][Hide abstract] ABSTRACT: Thymus transplants can correct deficiencies of the thymus epithelium caused by the complete DiGeorge syndrome or FOXN1 mutations.
However, thymus transplants were never used to correct T cell–intrinsic deficiencies because it is generally believed that
thymocytes have short intrinsic lifespans. This notion is based on thymus transplantation experiments where it was shown that
thymus-resident cells were rapidly replaced by progenitors originating in the bone marrow. In contrast, here we show that
neonatal thymi transplanted into interleukin 7 receptor–deficient hosts harbor populations with extensive capacity to self-renew,
and maintain continuous thymocyte generation and export. These thymus transplants reconstitute the full diversity of peripheral
T cell repertoires one month after surgery, which is the earliest time point studied. Moreover, transplantation experiments
performed across major histocompatibility barriers show that allogeneic transplanted thymi are not rejected, and allogeneic
cells do not induce graft-versus-host disease; transplants induced partial or total protection to infection. These results
challenge the current dogma that thymocytes cannot self-renew, and indicate a potential use of neonatal thymus transplants
to correct T cell–intrinsic deficiencies. Finally, as found with mature T cells, they show that thymocyte survival is determined
by the competition between incoming progenitors and resident cells.
Journal of Experimental Medicine 07/2012; 209(8):1401-1408. DOI:10.1084/jem.20120845 · 13.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The TCR-αβ/γδ CD8αα intraepithelial T lymphocytes (T-IEL) located in the gut mucosa of the small intestine are an abundant population believed to have a major role in ensuring the integrity of the gut wall. Here, we describe their unique characteristics and the controversies regarding the origin and differentiation of these T-IELs. We show how accumulated experimental evidence has finally arrived at a unifying concept, which demonstrates that these cells originate from early thymus precursors that have not yet undergone TCR rearrangement and TCR-αβ/γδ commitment. These precursors colonize the gut lamina propria during the perinatal period and complete rearrangements and TCR-αβ/γδ commitment while migrating to the epithelium. Therefore, the gut epithelium, which shares the same embryonic origin as the thymus epithelium, behaves as a primary lymphoid organ responsible for the differentiation of a major local T cell set.
[Show abstract][Hide abstract] ABSTRACT: The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.
Nature medicine 06/2011; 17(6):700-7. DOI:10.1038/nm.2366 · 28.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intestinal CD8αα intraepithelial T lymphocytes (T-IELs) have a key role in mucosal immunity and, unlike other T cells, were proposed to differentiate locally. In apparent contradiction, these cells were also shown to originate from a wave of thymus migrants colonizing the gut in the first 3 weeks after birth. We here identify previously uncharacterized very immature CD4(-)CD8(-)CD3(-)CD44(+)CD25(int) thymocytes, which have not yet rearranged their T-cell antigen receptor (TCR), as having the capacity to leave the thymus, migrate to the blood, colonize the gut, and reconstitute CD8αα T-IEL, and show that this cell set is fully responsible for the generation of the CD8αα T-IEL pool. Thus, although the thymus may be fundamental for efficient T-cell commitment, CD8αα T-IEL' complete TCR rearrangements and TCR-αβ/γδ lineage commitment must occur in the gut. These results demonstrate a major role of the gut environment as a primary lymphoid organ.