Characterization of CD4+ T cells in mouse bone marrow. I. Increased activated/memory phenotype and altered TCR Vβ repertoire

Abstract

A significant proportion of memory B cells home to bone marrow (BM) which is a major site of anamnestic antibody responses in mice. We hypothesized that memory T cells likewise accumulate in BM perhaps to provide help for antibody production, and that the compartment of CD4+ T cells in BM of unimmunized mice would be enriched for memory phenotype cells that might have been activated by environmental antigens. The phenotype of activated/memory CD4+ lymphocytes has been defined as CD44hi CD45RBlo CD62L-. Conversely, the phenotype of immunologically naive cells is CD44lo CD45RBhi CD62L+. Flow cytrometric analysis of tissue from normal, adult C57BL/6 mice identified 1-2 % CD3+CD4+ cells in BM. Up to 40 % of CD3+CD4+ cells in the BM expressed the activated/memory phenotype compared with < or = 10% in the spleen and lymph nodes. Analysis of TCR Vbeta repertoire revealed that expression of Vbeta3 and Vbeta7 genes was increased as much as fourfold in BM compared to the periphery; most of this increase was within the CD44hi T cells. The accumulation of activated/memory T cells and clonotypic expansion(s) was not seen in the BM of germ-free mice, indicating that it reflects the history of the animal's exposure to antigens. Finally, immunization of mice which express a transgenic T cell receptor specific for ovalbumin peptide resulted in appearance of antigen-specific T cells with activated/memory phenotype in the BM.

Normal hematopoiesis is maintained by activated bone marrow CD4+ T cells

“…Previous papers reported an unusual activation phenotype in BM T cells. [23][24][25] In line with these descriptions, we found that in normal BALB/c mice, CD4 ϩ BM T-cell populations are enriched with activated T cells as assessed by CD62L and CD45RB expression ( Figure 5A). These cells show a predominantly activated/memory phenotype (CD62L low CD45RB int/low ), indicating a previous antigenic stimulation.…”

“…Bone marrow T cells make up only 1% to 3% of BM microenvironment and have activated phenotype and semidiverse V␤ repertoire. [23][24][25] Moreover, it is still unclear if activation takes place in the periphery, in the bone marrow, or in both. Interestingly enough, in common gamma chain-deficient mice (␥ c Ϫ/Ϫ ) a deregulated activated CD4 ϩ T-cell population enhances BM hematopoiesis and promotes the appearance of extramedullary hematopoietic foci.…”

Linking immunity and hematopoiesis by bone marrow T cell activity

“…Thus, since to help hematopoiesis T cells must be activated, we looked at the activation status of these cells in the bone marrow of normal mice. In agreement with previous descriptions (17,19) we found an increased proportion of activated CD4 + T cells in mouse bone marrow -most of them showing an early activated phenotype (5).…”

“…We and others have found an increased number of activated T cells in mouse bone marrow (5,17,19,20). This is true for both CD4 + and CD8 + T cells.…”

“…The role of these unusual T cells in the bone marrow, specifically regarding hematopoiesis, has not been evaluated. The remaining two thirds are conventional αßTCR + T cells enriched in activated and memory CD4 + and CD8 + T cells (5,17,19,20). The potential of these cells as hematopoietin providers or their cytokine profile and the stimuli promoting their activation have never been investigated.…”