Genetic Dissection of Age‐Related Changes of Immune Function in Mice

Abstract

Understanding of the genetic basis of normal and abnormal development of the immune response is an enormous undertaking. The immune response, at the most minimal level, involves interactions of antigen presenting cells (APCs), T and B cells. Each of these cells produce cell surface and soluble factors (cytokines) that affect both autocrine and paracrine functions. A second level of complexity needs to consider the development of the macrophage/monocyte lineage as well as the production of the common lymphoid precursor which undergoes distinct maturation steps in the thymus and periphery to form mature T cells as well as in BM (BM) and lymphoid organs to form mature B cells. A third level of complexity involves the immune response to infectious agents including viruses and also the response to tumour antigens. In addition, there are imbalances that predispose to decreased responses (immunodeficiencies) or increased responses (autoimmunity). A fourth level of complexity involves attempts to understand the differences in the immune response that occurs at a very young age, in adults, and at a very old age. This review will focus on the use of C57BL/6 J X DBA/2 J (BXD) recombinant inbred (RI) strains of mice to map genetic loci associated with the production of lymphoid precursors in the BM, development of T cells in the thymus, and T-cell responses to stimulation in the peripheral lymphoid organs in adult and in aged mice. Strategies to improve the power and precision in which complex traits such as the age-related immune response can be mapped is limited with the current set of 35 strains of BXD mice. Strategies to increase these strains by generating recombinant intercross (RIX) strains of mice are being developed to enable this large set of lines to detect quantitative trait loci (QTLs) with a much higher consistency and statistical power. More importantly, the resolution with which these QTLs can be mapped would be greatly improved and, in many cases, adequate to carry out direct identification of candidate genes. It is likely that, given the complexity of the immune system development, the number of cells involved in an immune response, and especially the changes in the immune system with ageing, mapping hundreds of genes will be required to fully understand age-related changes in the immune response. This review outlines ongoing and future strategies that will enable the mapping and identification of these genes.

BXD recombinant inbred mice represent a novel T cell–mediated immune response tumor model

“…One advantage of using the BXD RI strains as a model of tumor growth is that these cell lines are the focus of ongoing studies to identify the mechanisms underlying differences in immune responses 35. The present results lend further support to the concept that T cells can play critical roles in limiting tumor growth and mediating tumor regression.…”

A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells

“…50,51 We found that aged mice of all strains showed a highly significant (P Ͻ .001) decline of T cells in blood compared with younger animals of the same strain ( Figure 1). However, aged D2 mice showed a significantly (P ϭ .02) higher level of T cells (25.4% Ϯ 5.7%) compared with aged B6 (17.6% Ϯ 6.7%).…”

Generating Embryonic Stem Cells from the Inbred Mouse Strain DBA/2J, a Model of Glaucoma and Other Complex Diseases

“…AKXD strains have been used to study a variety of diseases including murine lymphoma and glaucoma [24], [25]. The more widely used BXD strains have been used to understand the genetics of a variety of diseases and biological systems including aging, the immune system and iron regulation [26], [27], [28], [29], [30]. Much of this work has been made available through GeneNetwork (formerly WebQTL ) an on-line resource to study complex gene networks and phenotypes [31].…”