Gene regulatory network of memory B cell and long-lived plasma cell differentiation

The generation of long-lasting humoral immunity is the purpose of almost all vaccines. Long-lasting humoral immunity is mediated through antibodies produced by plasma cells (PCs) and memory B cells (MBCs). Despite the outstanding success of vaccinations overall, many clinical and experimental vaccines fail to induce long- lasting humoral immunity. One key example is the influenza vaccine, which requires administration every year. Upon encountering a foreign antigen, antigen-specific B cells proliferate and differentiate into the germinal center (GC) B cells and subsequently generate PCs and MBCs. B cell receptor and CD40 receptor signaling result in the activation of NFkB in GC B cells. It is well established that transcription factors NFkB cRel and RelA are critical for physiological B cell responses and that their misregulation leads to B cell-mediated diseases. cRel and RelA are essential for generating GC B cells and PCs. The activation of cRel and RelA depends on the degradation of NFkB inhibitors, IkBs. IkBa and IkBe have different binding preferences to cRel and RelA. IkBa binds to RelA-containing dimer (RelA:p50) with a higher affinity than cRel-containing dimer (cRel:p50), whereas IkBe binds to cRel:p50 with a higher affinity than RelA:p50. The network of IkBa, IkBe, cRel, and RelA is defined here as the NFkB signaling network. The role of the NFkB signaling network in regulating affinity maturation and generating PCs versus MBCs is unknown. In this project, we will define the role of the NFkB signaling network in regulating affinity maturation and in the generation of PCs versus MBCs. The objective of Aim 1 is to define how IkBa and IkBe regulate affinity maturation and the generation of PCs and MBCs. The objective of Aim 2 is to identify how cell surface receptors regulate the abundance of IkBa and IkBe and thus control cRel and RelA activation in GC B cells. The objective of Aim 3 is to determine whether the vaccine-induced response of IkBa- deficient and IkBe-deficient mice can enhance humoral immunity against influenza infection. The proposed research is innovative because it defines the discrete role of IkBa and IkBe in regulating the fate of GC B cells. This work uses newly generated cRel and RelA fluorescence reporter mice and IkBe and IkBa knock-out mice. The proposed research is expected to define the mechanism that allows the NFkB signaling network to controll different gene regulatory programs within phenotypically-identical GC B cells to regulate affinity maturation, as well as the generation of PCs and MBCs. The study will reveal new insights into the generation of long-lived humoral immunity and improve immunity against influenza. Project Number: 1R01AI186945-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Koushik Roy | Institution: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, SALT LAKE CITY, UT | Award Amount: $625,348 | Activity Code: R01 | Study Section: Adaptive Immunity Study Section[AI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18694501A1