Foxp3+ CD4 regulatory T cells (T regs) maintain immune tolerance to self. Exactly how do they do it, no one really knows. Studies have described so many different mechanisms of T regs function that one can only wonder whether these cells really belong to one family.
Most likely, T regs may function in a tissue-specific manner as proposed by P. Matzinger and T. Kamala. New study published in Nature Immunology may support this hypothesis.
This study is a combined effort by French and German scientists. Here, the authors have examined the role of protein kinases in T regs function. Initial experiments showed that protein kinase, CK2 (casein kinase 2), was the most up-regulated kinase in activated T regs compared to effector T cells.
Next, the authors generated a mouse model carrying Foxp3-specific deletion of CK2 in T regs by crossing Foxp3-cre mice with CK2 fl/fl mice.
Interestingly, analysis of different tissues in Foxp3-cre CK2 fl/fl mice revealed that only lung tissue was affected by Foxp3-specific CK2 deletion in T regs.
Further analyses revealed that Foxp3-specific deletion of CK2 in T regs resulted in selective increase in type 2 immune signature in lung draining lymph nodes and in serum.
In fact, spontaneous lung inflammation in naive Foxp3-cre CK2 fl/fl mice was comparable to allergic lung inflammation (asthma) in antigen sensitized control mice.
However, surprisingly, T regs homing into lung tissue was not affected by Foxp3-specific CK2 deletion in T regs. More detailed analysis of T regs from Foxp3-cre CK2 fl/fl mice revealed selective up-regulation of inhibitory receptor ILT3.
The authors showed that ILT3 expression in CK2-deficient T regs could dampen TCR signalling in T regs.
Finally, the authors showed that CK2 deletion in T regs led to selective increase in numbers of type 2 response promoting IRF4+ PD-L2+ dendritic cells (DCs).
In summary, these results indicate that CK2 deletion in T regs induces ILT3 up-regulation and attenuation of TCR signaling in lung-tissue T regs, leading IRF4+ PD-L2+ dendritic cells (DCs) expansion and type II inflammation in the lung.
How these results advance our knowledge in Foxp3+ T cells? No data are provided to explain why lung-tissue T regs were so selectively affected by CK2 deletion or how IRF4+ PD-L2+ DCs are amplified. Very interesting and very strange.
Let me know what do you think about this study.