Developmental Immunology and Aging

The Richard and Kenneth Skodnek Laboratory

B-cell homeostasis and aging

B cell develop in the bone marrow (BM), and after negative and positive selection mature to the periphery and differentiate to one of the following subpopulations: follicular, B-1 and marginal zone. Continuous B cell output from the BM replenishes the loss of B cells in the periphery and steady state B cell numbers in the adult are achieved and maintained by means of equal production and loss rates. This cellular homeostasis, however, does not last for life and is dramatically changing with aging. Aging is associated with a decline in B-lymphopoiesis in the BM and accumulation of long-lived B-cells in the periphery. The most important immunological manifestations that are resultant of these changes include poor responsiveness to new or evolving pathogens, and reduced efficacy of vaccination. Aging of the B lineage is thought as a progressive and irreversible process resulting from acquisition of intrinsic defects in hematopoietic stem cells. We discovered that aging in the B lineage reflects homeostatic pressures that are set by the long-lived memory cells that accumulate in the periphery. We showed that mutant mice with chronic B cell deficiency are devoid of senescence in the B lineage. Moreover, we showed that removing of these cells in old mice revives B lymphopoiesis in the BM, rejuvenates the peripheral B cell compartment and restores the competence to respond to new antigenic challenge. Hence, our results are the first demonstration that physiological aging can in fact be reversed and therefore have also wide multidisciplinary impact.

Current research focuses in the following directions:

1.Identifying the cross-talk mechanism between peripheral B cells and progenitors in the BM

2.Implications of B cell depletion to enhance immunity in elderly population

3.Defining of an aging B cell signature.

microRNAs in regulating positive and negative selection of B lineage cells.

A hallmark of B cell lymphopoesis in the bone marrow (BM) is the assembly of the BCR, which comprises a central molecule in determination of B cell fate decision. Autoreactivity in the B lineage arises as a consequence of random rearrangements of immunoglobulin (Ig) genes. A major mechanism to extinguish autoreactivity (negative selection) is by renewing the Ig genes rearrangements and replacing the receptor specificity, a process called receptor editing. Our laboratory has showed that further maturation of non-self B cells depend on the generation of appropriate ligand-independent BCR signals in a process referred as positive selection. We showed that inappropriate ligand-independent signals impose developmental arrest, block positive selection and activate receptor editing. We further showed that these tonic BCR signals control the expression of recombination activating genes (RAGs) and the activation of receptor editing. Thus, our studies were first to show the involvement of receptor editing in both positive and negative selection of B cells in the BM. Another major mechanism for negative selection is activation induced cell death (AICD). Immature B cells encountering self-antigen activate cellular pathway to initiate apoptosis, where c-myc oncogene expression and regulation has a major role in the determination of the cells' fate. The research conducted in the lab attempts to study how multiple intracellular pathway coordinate in the regulation of BCR-mediated AICD. One major pathway that controls B cell selection is the PI3K. Yet the physiological mechanism by which PI3K activity is regulated is unclear. Recent research in the lab focuses in elucidating novel mechanisms by which microRNAs regulate PI3K activity for positive and negative selection.

Current research focuses in the following directions:

1.Alteration of BCR signaling to increase AICD in apoptosis-refractory B lineage cells.

2.Regulation of AICD in B lineage cells by microRNA

3.Biochemical pathways and microRNA controlling expression of RAG genes in B lineage cells.