A new resting place

Unlike memory CD8⁺ T cells and plasma cells, which reside in bone marrow niches, it had been presumed that memory CD4⁺ T cells constantly circulate in the body for surveillance. Now, Tokoyoda and colleagues show that memory CD4⁺ T cells do in fact reside and rest in the bone marrow, where they associate with interleukin-7 (IL-7)-expressing stromal cells.

The authors tracked the tissue distribution of antigen-specific memory (CD44^hiCD62L⁻) CD4⁺ T cells in mice and found that 4 days after antigen immunization, activated antigen-specific CD44^hiCD4⁺ T cells were only present in the spleen and draining lymph nodes. However, from day 60 onwards more than 80% of the antigen-specific memory CD4⁺ T cells had relocated to the bone marrow, a process that depended on α2 integrin expression by the T cells. Unlike most spleen CD44^hiCD62L⁻CD4⁺ T cells, bone marrow CD44^hiCD62L⁻CD4⁺ T cells could be characterized by high expression levels of LY6C.

A comparison of the gene expression profile of spleen and bone marrow memory CD4⁺ T cells showed that 96% of the genes that were differentially expressed were downregulated in bone marrow memory CD4⁺ T cells. In addition, bone marrow memory CD4⁺ T cells did not proliferate in the steady state, so together these observations indicate that these cells are in a resting state. Further analysis showed that ∼95% of the antigen-specific memory CD4⁺ T cells in the bone marrow colocalized individually with VCAM1⁺ stromal cells that expressed IL-7, a cytokine that is essential for the maintenance of CD4⁺ T cell memory. The authors estimated the capacity of the mouse bone marrow for memory CD4⁺ T cells to be about 1% of the bone marrow cells, which corresponds to the percentage of VCAM1⁺ IL-7-producing stromal cells in the bone marrow.

Finally, the authors showed that in a secondary immune response bone marrow memory CD4⁺ T cells expressed interferon-γ and CD40 ligand faster and at higher levels than spleen memory CD4⁺ T cells and that only bone marrow memory CD4⁺ T cells could provide help for the production of high-affinity antibodies by B cells.

So, the data indicate that memory CD4⁺ T cells reside in dedicated bone marrow survival niches in a resting state but can be quickly reactivated to provide fast and efficient help to B cells during secondary immune responses.