Edited by Klaus Rajewsky, Max Delbrück Center for Molecular Medicine, Berlin, Germany, and approved May 16, 2014 (received for review October 3, 2013)
Memory T cells are essential components of immunological memory. In the apparent absence of antigen, numbers of recirculating antigen-specific memory T cells dwindle, provoking the question of whether there is immunological memory without memory T cells. Here we show that human memory T cells can reside in the bone marrow as resting cells in terms of proliferation, transcription, and mobility. The repertoire of bone marrow memory T cells is enriched for systemic pathogens representing persistent, recent, and childhood challenges. In terms of absolute numbers, memory T cells specific for systemic antigens are maintained predominantly in the bone marrow, in particular those representing historic encounters.
In the bone marrow, a population of memory T cells has been described that promotes efficient secondary immune responses and has been considered to be preactivated, owing to its expression of CD69 and CD25. Here we show that human bone marrow professional memory T cells are not activated but are resting in terms of proliferation, transcription, and mobility. They are in the G0 phase of the cell cycle, and their transcriptome is that of resting T cells. The repertoire of CD4+ bone marrow memory T cells compared with CD4+ memory T cells from the blood is significantly enriched for T cells specific for cytomegalovirus-pp65 (immunodominant protein), tetanus toxoid, measles, mumps, and rubella. It is not enriched for vaccinia virus and Candida albicans-MP65 (immunodominant protein), typical pathogens of skin and/or mucosa. CD4+ memory T cells specific for measles are maintained nearly exclusively in the bone marrow. Thus, CD4+ memory T cells from the bone marrow provide long-term memory for systemic pathogens.
↵1A.R. and J.D. contributed equally to this work.
Author contributions: A.R. and J.D. designed research; A.O., K.W., and J.D. performed research; S.R., P.v.R., G.W., A.A.K., R.K., S.D., C.S., K.T., M.J.R., and G.S. contributed new reagents/analytic tools; A.S. and H.-D.C. wrote the ethical application; A.O., J.R.G., Z.F., M.A.M., and J.D. analyzed data; A.O. and J.D. interpreted data and generated figures; and A.R. and J.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data discussed in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE50677).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1318731111/-/DCSupplemental.
Freely available online through the PNAS open access option.
