Selection of the B cell repertoire in senescence

Project: Research project

Description

B lymphopoiesis is severely compromised in murine senescence. The defect in B lymphopoiesis in senescence predominantly "maps" to the pro-B to pre-B cell transition, a stage critically dependent upon signaling via the pre-B cell receptor (ix/_.5/VpreB; preBCR) and the growth cytokine IL-7. We propose that in senescence the development ofpre-B cells is subject to increasingly stringent negative selection. This results primarily from decline in expression of the preBCR, poor responses to IL-7, and increased susceptibility to apoptosis. Rather than random loss of pre-B cells in old age, we propose contraction of the pre-B cell pool in a clone-specific manner. Preferentially selected would be those few pre-B ceils which maintain the capacity
to undergo preBCR/IL-7 mediated growth and survival. This results in a "reshaping" of the pre-B and immature B cell specificity repertoires in senescence. To address this hypothesis, we propose 3 Specific Aims. Specific Aim 1 asks "Is the loss of pre-B cells in old age random or clone-specific?". In this Specific Aim, Vh family use, CDR3 diversity, capacity to express functional preBCRs, and the role of the microenvironment in altering B lineage development and "read-out" of the antibody repertoire will be addressed. Specific Aim 2 asks "Does 'repertoire reshaping' at the pre-B stage affect the read-out of the B cell repertoire in old age?". Here, Vh use and CDR3 diversity will be assessed in immature B cells from aged mice and compared with that of pre-B cells. Furthermore, the antibody specificity of immature B cells in aged mice will be assessed and the fate of these immature B cells in the periphery will be determined.
Specific Aim 3 asks "Does apoptotic stress result in changes in the pre-B and immature B cell repertoires in senescence?". Sensitivity to apoptosis and the expression of apoptotic/survival molecules in aged B cells will be determined. The effects of the environment on apoptotic susceptibility among aged B lineage cells will be assessed. Finally, the role of apoptosis in modulating the pre-B/immature B cell repertoires in senescence will be tested. These studies will advance understanding of the immune defects which accompany old age and their cellular and molecular mechanisms.
StatusFinished
Effective start/end date9/30/048/31/18

Funding

  • National Institutes of Health: $294,127.00
  • National Institutes of Health: $277,951.00
  • National Institutes of Health: $84,196.00
  • National Institutes of Health: $295,880.00
  • National Institutes of Health: $303,000.00
  • National Institutes of Health: $281,552.00
  • National Institutes of Health: $287,299.00
  • National Institutes of Health: $294,127.00
  • National Institutes of Health: $214,900.00
  • National Institutes of Health: $303,000.00
  • National Institutes of Health: $294,127.00
  • National Institutes of Health: $306,000.00

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B-Lymphoid Precursor Cells
Pre-B Cell Receptors
B-Lymphocytes
Surrogate Immunoglobulin Light Chains
Lymphopoiesis
Interleukin-7
Pneumonia
Antibody-Producing Cells
Down-Regulation
Antibodies
Antibody Formation
Phosphorylcholine
Immunoglobulin Heavy Chains
Apoptosis
Cytokines
Natural Killer Cells
Bone Marrow
Spleen
Clone Cells
Antibody Specificity

ASJC

  • Medicine(all)