Suppressive effects of monocytic cells and transforming growth factor-beta on natural killer cell differentiation in autoimmune viable motheaten mutant mice
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Published on: January 9, 2018
1Merck Sharp and Dohme Research Laboratories, Rahway, NJ 07065.
Abstract:
Viable motheaten (mev) mice are homozygous for a recessive single gene mutation at chromosome 6. These mice develop numerous inflammatory and arthritic syndromes and exhibit abnormal B cell functions as well as lower T and NK cell activity. In this study, the differentiation of NK cells in mev mice was examined to elucidate the underlying basis for decreased NK activity. Although NK cells appear to be present in mev mice, their activity was demonstrable only when the spleen cells were enriched by nylon wool passage. Similarly bone marrow cells from these mice could be shown to contain precursors of NK cells when they were passed over nylon wool and transplanted into irradiated recipients. The adherent cells from both the spleen and bone marrow of mev mice suppressed the differentiation of NK cells from normal splenic populations. These suppressive adherent cells were F4/80(+), AsGm-1(+), Qa-5(+), and NK-1.1(+). They were not cytolytic when cultured in IL-2. Antibodies to a number of cytokines, such as IFN-alpha, -beta, and gamma, or TNF-alpha, could not reverse the suppressive effect of the adherent cells. Addition of anti-TGF-beta antibody could, however, overcome the suppression, suggesting that TGF-beta was partly responsible for the defective NK differentiation in the mev mice.
Insights
Motheaten (mev) mice have defective Natural Killer (NK) cell activity due to suppressive adherent cells. Transforming growth factor-beta (TGF-β) from these cells impairs NK cell differentiation, offering a target for therapeutic intervention.
Area of Science:
- Immunology
- Genetics
Background:
- Motheaten (mev) mice exhibit inflammatory and arthritic conditions with impaired immune cell function.
- Reduced Natural Killer (NK) cell activity is a noted characteristic of mev mice.
Purpose of the Study:
- To investigate the basis of decreased NK cell activity in mev mice.
- To identify the cellular and molecular mechanisms underlying defective NK cell differentiation.
Main Methods:
- Analysis of NK cell differentiation in spleen and bone marrow cells from mev mice.
- Enrichment of spleen cells using nylon wool passage to assess NK cell precursors.
- Co-culture experiments with adherent cells from mev mice and normal splenic populations.
- Characterization of suppressive adherent cells using surface markers (F4/80, AsGm-1, Qa-5, NK-1.1).
- Testing the effect of cytokine-neutralizing antibodies, including anti-TGF-beta antibody.
Main Results:
- NK cell precursors were present in mev mice but required enrichment for functional assessment.
- Adherent cells from mev mice suppressed NK cell differentiation from normal spleen cells.
- These suppressive cells expressed specific surface markers and were not cytolytic.
- The suppressive effect was partially reversed by anti-TGF-beta antibody, but not by antibodies against IFN or TNF-alpha.
Conclusions:
- Defective NK cell differentiation in mev mice is mediated by suppressive adherent cells.
- Transforming growth factor-beta (TGF-β) plays a significant role in this suppression.
- Targeting TGF-β may offer a therapeutic strategy for immune dysfunction in mev mice.
