Regulatory T cell subsets are differentially dependent on CD28 for their proliferation.

Area of Science:

• Immunology
• Cell Biology
• T cell biology

Background:

• CD28 is crucial for maintaining regulatory T cell (Treg) numbers by promoting their development and proliferation.
• Treg subsets, thymus-derived Tregs (tTregs) and peripherally-derived Tregs (pTregs), exhibit differential CD28 dependency for their development.
• This suggests CD28 may also influence the homeostasis of distinct Treg subsets differently.

Purpose of the Study:

• To investigate the differential roles of CD28 in the proliferation and homeostasis of tTregs and pTregs.
• To elucidate the specific CD28 signaling pathways involved in Treg proliferation under varying conditions.

Main Methods:

• Analysis of Treg subsets in CD28-deficient mice and wild-type controls.
• Assessment of Treg proliferation under steady-state and lymphopenic conditions.
• Utilizing mutant CD28 knock-in mice to dissect signaling pathways.

Main Results:

• Both tTregs and pTregs showed reduced proliferation in CD28-deficient mice, indicating an intrinsic CD28 defect.
• CD28 regulated the massive proliferation of both Treg subsets during lymphopenia.
• Steady-state tTreg proliferation was CD28-dependent, while pTreg proliferation was not.
• pTreg proliferation in lymphopenia required the Lck-NFκB pathway of CD28, whereas tTregs needed an additional unknown pathway.

Conclusions:

• CD28 dependency for Treg proliferation varies significantly between tTregs and pTregs.
• The immune environment, such as lymphopenia, alters CD28's role in Treg proliferation.
• Distinct CD28 signaling pathways are engaged by different Treg subsets depending on the context.