Cell division and differentiation of lymphocytes

Cell division and differentiation of lymphocytes

Today, I am reading a great review article about T cell division and differentiation. So like to share it here.

Adaptive immunity requires the proliferation of a few antigen-reactive lymphocytes into a large population of effector cells. Cell division and differentiation are the key progress for T-cell to proliferate and turn into responsive effector cells. The latest review published on Nature Reviews Immunology by Dr. Andrew D. Wells and Dr. Peter A. Morawski suggested that cyclin-dependent kinases (CDKs)Nepicastat may play some new roles of linking T cell division and differentiation.

There are 20 members in the cyclin-dependent kinase family that specifically phosphorylate serine/threonine amino acids of target proteins. These CDKs have been known as critical regulators in cell cycle progression. CDK1 is the only CDK required for mitotic cell cycle progression. Others CDKs like interphase CDKs contribute to driving the differentiation despite the indicated role in regulation of cell cycle. Further more, all of them likely compensate for one another in fulfilling their roles in cells.

During lymphocyte differentiation the acquisition of differentiation markers and capability of secreting effector cytokines are correlated with the numbers of cell divisions achieved during the primary stimulation. In other words, the more rounds of cell cycle completed by T cells upon primary response, the more likely they will produce effctor cytokines. There are three non-mutually exclusive models that have suggested the link between T cellPJ34 division and differentiation.

One model suggests that epigenetic modification of T cell effector genes occurs during S phase and mitosis phase. The second model proposes that cell division offers asymmetrical segregation of lineage-specific transcription factors. The third model postulates that CDKs and/or other cell cycle-coupled kinase pathways directly regulates effector and/or memory cell gene expression. Dr. Wells and Dr. Morawski focused on the third model that suggests that CDKs directly regulate factors involved in T cell differentiation.

The first key factor mentioned is p27, an anergy vs differentiation checkpoint sensor. P27, at high level of expression in quiescent T cells, can be phosphorylated by AKT upon co-stimulation of T cell receptor (TCR) and CD28, which leads to its release from CDK-cyclin complexes and escape from nucleus into cytoplasm. CDK2 phosphorylates p27 thereby targeting p27 for ubiquitylation and degradation. However, in the absence of CD28 co-stimulation, a TCR signal can not activate AKT and CDK2 to down regulate p27 in T cells. As a result, These T cells failed to differentiate and instead remained anergic. High p27 levels are critical for cytokine IL-2 expression repression and p27-deficient CD4+ T cells can differentiate into fully functional effector cells without CD28 co-stimulation. All the evidence have indicated that p27 is an anergic sensor that could alter the CD28 co-stimulated T cell differentiation.

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