CCL25
C-C motif chemokine 25 precursor (Chemokine TECK) (Small-inducible cytokine A25) (Thymus-expressed chemokine) [SCYA25] [TECK]
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The chemokines CCL25 and CCL28, which promote immune cell migration, are primarily expressed in the small and large intestines and play critical roles in sustaining gut immunity. In particular, these chemokines are closely related to intestinal IgA secretion. However, there is no research regarding the effects of aging on CCL25 and CCL28 expression and function. Therefore, in the present study, we investigated the effects of aging on production of CCL25 and CCL28, and on gut immunity, especially IgA secretion, using young and aged female mice. By aging, the levels of small intestinal mRNA and protein of CCL25 lowered, while these levels of CCL28 in colon became higher. Moreover, the number of IgA-antibody secreting cells (IgA-ASCs) and total IgA concentration decreased in the small intestine due to the age-associated reduction of CCL25. In contrast, colonic IgA production was increased due to up-regulation of CCL28, while the number of colonic IgA-ASCs was unchanged with aging. These results clearly demonstrate that aging-associated decrease in small intestinal CCL25 production and increase in colonic CCL28 production c be involved in aging-associated deterioration of gut immunity.
Keywords
- Aging
- CCL25
- CCL28
- Gut immunity
- IgA
Aging is associated with reduced numbers of all thymocyte sub-populations, including early T-cell progenitors. However, it is unclear if this is due to inadequate recruitment of lymphohematopoietic progenitor cells (LPCs) to the aged thymus or to abnormal development of T cells within the thymus. We found that LPCs from young mice were recruited equally well to the thymi of young or aged mice and that thymic stromal cells (TSCs) from young and old mice expressed similar levels of P-selectin and CCL25, which are believed to mediate recruitment of LPCs to the adult thymus. However, the number of recruited thymocytes in old thymus was markedly reduced after two weeks, indicating that T-cell development or proliferation is defective in the aged thymus. We also found that LPCs from aged and young mice have similar capacities to seed a fetal thymus that was transplanted under the kidney capsule. Thymic epithelial cells (TECs) in aged mice had lower proliferative capacity and higher rate of apoptosis, compared with findings in young animals. In addition, immunofluorescence staining with antibodies to cortical and medullary TECs revealed that aged thymi had a disorganized thymic stromal architecture, combined with reduced cellularity of the medulla, and apoptosis of thymocyte sub-populations in the medullary microenvironment was increased, compared with that in young mice. We conclude that aging does not impair recruitment of LPCs to the thymus, but is characterized by abnormalities in thymic epithelial architecture, especially medullary TEC function that may provide sub-optimal support for thymic development of LPCs.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Cell Proliferation
- Chemokines, CC
- Epithelial Cells
- Fetus
- Hematopoietic Stem Cells
- Lymphoid Progenitor Cells
- Mice
- Mice, Inbred C57BL
- P-Selectin
- Thymus Gland
Chemokines appear to have an important role in the seeding of lymphoid progenitors in the thymus, the regulation of the coordinated movements of the maturing T cells within this organ, and the egress of the resulting naive T cells to secondary lymphoid organs. CCR9, the specific receptor for the beta-chemokine TECK/CCL25, is selectively expressed in thymus, lymph node, and spleen. Using a specific anti-CCR9 polyclonal antibody, K629, and a semiquantitative reverse transcriptase-polymerase chain reaction procedure, a detailed study of CCR9 expression in the thymus and secondary lymphoid organs was performed. The results show that CD4( )CD8( ) double-positive thymocytes have the highest CCR9 expression in thymus. Single-positive CD8( ) thymocytes continue to express this receptor after abandoning the thymus as mature naive T cells, as suggested by the existence of a CD8( )CD69(low)CD62L(high) CCR9( ) cell subset. Consistent with this, CD8( ) lymphocytes from lymph nodes, spleen, and Peyer patches express a functional CCR9, as its expression correlates with migration in response to CCL25. Conversely, CD4( ) thymocytes lose CCR9 before abandoning the thymus, and CD4( ) T cells from secondary lymphoid organs also lack CCR9 expression. Analysis of CCR9 expression in thymocytes from mice of different ages showed that CCR9 levels are affected by age, as this receptor is more abundant, and its response to CCL25 is more potent in newborn animals. Collectively, these results suggest that CCR9 has a role in thymocyte development throughout murine life, with clear differences between the CD4( ) and CD8( ) lineages.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cell Lineage
- Chemokines, CC
- Chemotaxis
- DNA-Binding Proteins
- Gene Expression Profiling
- Lymph Nodes
- Lymphoid Tissue
- Mice
- Mice, Inbred BALB C
- Mice, Knockout
- Muromonab-CD3
- Peyer's Patches
- RNA, Messenger
- Rabbits
- Receptors, CCR
- Receptors, Chemokine
- Recombinant Fusion Proteins
- Reverse Transcriptase Polymerase Chain Reaction
- Spleen
- T-Lymphocyte Subsets
- Thymus Gland
- Transfection