The role of the gut as a primary lymphoid organ: CD8αα intraepithelial T lymphocytes in euthymic mice derive from very immature CD44+ thymocyte precursors

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.

Role of the gut as a primary lymphoid organ

“…Complementary evidence allowed us to determine at what stage of differentiation the TN precursors could leave the thymus and give rise to CD8␣␣ T-IEL. Only CD44 + TN cells fully reconstituted the CD8␣␣ T-IEL compartment with a Thy1 +/− phenotype and the TCR-␣␤/TCR-␥␦ representation seen in euthymic mice [42]. After thymus transplant, we could find early precursors of thymic origin in the blood and in the gut LP [42].…”

“…Direct studies of immature TN subsets isolated from the neonatal thymus also showed that the TN1-TN2 subset had the potential to leave the thymus and colonize the gut. We showed that during the TN1-TN2 transition, thymocytes strongly upregulate the expression of ␣4␤7 integrin [42] and also express CCR9 (unpublished), both of which are required for homing to the gut. They also express a high frequency of S1p1, which codes for the receptor of sphingosine-1-phosphate, which is required for thymus egress [42].…”

“…We showed that during the TN1-TN2 transition, thymocytes strongly upregulate the expression of ␣4␤7 integrin [42] and also express CCR9 (unpublished), both of which are required for homing to the gut. They also express a high frequency of S1p1, which codes for the receptor of sphingosine-1-phosphate, which is required for thymus egress [42]. Moreover, the location of TN1-TN2 transitional cells in the thymus also favors egress, which is described as taking place through capillaries located at the corticomedullary junction.…”

“…Most of the Lin − precursors detected in the blood corresponded to a previously uncharacterized cell type in the transition between the CD44 + CD25 − (TN1) and CD44 + CD25 + (TN2) thymocyte sets (CD44 + CD25 int TN1-TN2 transitional cells). These precursors expressed a high frequency of Rag1 [42]. Direct studies of immature TN subsets isolated from the neonatal thymus also showed that the TN1-TN2 subset had the potential to leave the thymus and colonize the gut.…”

“…Only CD44 + TN cells fully reconstituted the CD8␣␣ T-IEL compartment with a Thy1 +/− phenotype and the TCR-␣␤/TCR-␥␦ representation seen in euthymic mice [42]. After thymus transplant, we could find early precursors of thymic origin in the blood and in the gut LP [42]. Most of the Lin − precursors detected in the blood corresponded to a previously uncharacterized cell type in the transition between the CD44 + CD25 − (TN1) and CD44 + CD25 + (TN2) thymocyte sets (CD44 + CD25 int TN1-TN2 transitional cells).…”