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      HIV-1 persistence in CD4 + T cells with stem cell-like properties

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          Abstract

          Cellular HIV-1 reservoirs that persist despite antiretroviral treatment are incompletely defined. We show that during suppressive antiretroviral therapy, CD4 + T memory stem cells (T SCM) harbor high per-cell levels of HIV-1 DNA, and make increasing contributions to the total viral CD4 + T cell reservoir over time. Moreover, phylogenetic studies suggested long-term persistence of viral quasispecies in CD4 + T SCM cells. Thus, HIV-1 may exploit stem cell characteristics of cellular immune memory to promote long-term viral persistence.

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          IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors.

          Nicoletta Cieri, Barbara Camisa, Fabienne Cocchiarella … (2013)
          Long-living memory stem T cells (T(SCM)) with the ability to self-renew and the plasticity to differentiate into potent effectors could be valuable weapons in adoptive T-cell therapy against cancer. Nonetheless, procedures to specifically target this T-cell population remain elusive. Here, we show that it is possible to differentiate in vitro, expand, and gene modify in clinically compliant conditions CD8(+) T(SCM) lymphocytes starting from naive precursors. Requirements for the generation of this T-cell subset, described as CD62L(+)CCR7(+)CD45RA(+)CD45R0(+)IL-7Rα(+)CD95(+), are CD3/CD28 engagement and culture with IL-7 and IL-15. Accordingly, T(SCM) accumulates early after hematopoietic stem cell transplantation. The gene expression signature and functional phenotype define this population as a distinct memory T-lymphocyte subset, intermediate between naive and central memory cells. When transplanted in immunodeficient mice, gene-modified naive-derived T(SCM) prove superior to other memory lymphocytes for the ability to expand and differentiate into effectors able to mediate a potent xenogeneic GVHD. Furthermore, gene-modified T(SCM) are the only T-cell subset able to expand and mediate GVHD on serial transplantation, suggesting self-renewal capacity in a clinically relevant setting. These findings provide novel insights into the origin and requirements for T(SCM) generation and pave the way for their clinical rapid exploitation in adoptive cell therapy.
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            Superior T memory stem cell persistence supports long-lived T cell memory.

            Jason Brenchley, Kaimei Song, Nichole Klatt … (2013)
            Long-lived memory T cells are able to persist in the host in the absence of antigen; however, the mechanism by which they are maintained is not well understood. Recently, a subset of human T cells, stem cell memory T cells (TSCM cells), was shown to be self-renewing and multipotent, thereby providing a potential reservoir for T cell memory throughout life. However, their in vivo dynamics and homeostasis still remain to be defined due to the lack of suitable animal models. We identified T cells with a TSCM phenotype and stem cell-like properties in nonhuman primates. These cells were the least-differentiated memory subset, were functionally distinct from conventional memory cells, and served as precursors of central memory. Antigen-specific TSCM cells preferentially localized to LNs and were virtually absent from mucosal surfaces. They were generated in the acute phase of viral infection, preferentially survived in comparison with all other memory cells following elimination of antigen, and stably persisted for the long term. Thus, one mechanism for maintenance of long-term T cell memory derives from the unique homeostatic properties of TSCM cells. Vaccination strategies designed to elicit durable cellular immunity should target the generation of TSCM cells.
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              Host-reactive CD8+ memory stem cells in graft-versus-host disease.

              Elizabeth Hexner, Gerard Joe, Ronald G. Emerson … (2005)
              Graft-versus-host disease (GVHD) is caused by alloreactive donor T cells that trigger host tissue injury. GVHD develops over weeks or months, but how this immune response is maintained over time is unknown. In mouse models of human GVHD, we identify a new subset of postmitotic CD44(lo)CD62L(hi)CD8(+) T cells that generate and sustain all allogeneic T-cell subsets in GVHD reactions, including central memory, effector memory and effector CD8(+) T cells, while self-renewing. These cells express Sca-1, CD122 and Bcl-2, and induce GVHD upon transfer into secondary recipients. The postmitotic CD44(lo)CD62L(hi)CD8(+) T cells persist throughout the course of GVHD, are generated in the initial phase in response to alloantigens and dendritic cells and require interleukin-15. Thus, their long life, ability to self-renew and multipotentiality define these cells as candidate memory stem cells. Memory stem cells will be important targets for understanding and influencing diverse chronic immune reactions, including GVHD.
              Article 0 comments Cited 114 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9502015
                Journal ID (pubmed-jr-id): 8791
                Journal ID (nlm-ta): Nat Med
                Journal ID (iso-abbrev): Nat. Med.
                Title: Nature medicine
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Nihms-submitted: 22 January 2014
                Publication date (Electronic): 12 January 2014
                Publication date (Print): February 2014
                Publication date PMC-release: 01 August 2014
                Volume: 20
                Issue: 2
                Pages: 139-142
                Affiliations
                [1 ]Infectious Disease Division, Massachusetts General Hospital, Boston, MA
                [2 ]Ragon Institute of MGH, MIT and Harvard, Cambridge, MA
                [3 ]AIDS Research Center, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, P. R. China
                [4 ]Infectious Disease Division, Brigham and Women’s Hospital, Boston, MA
                [5 ]Department of Electrical and Computer Engineering, University of Delaware, Newark, DE
                [6 ]Howard Hughes Medical Institute, Chevy Chase, MD
                Author notes
                Corresponding author: Mathias Lichterfeld, M. D., Ph. D., Assistant Professor of Medicine, Infectious Disease Division, Massachusetts General Hospital, 55 Fruit Street, Jackson 5, Boston, MA 02114, USA
                Article
                Manuscript ID: NIHMS547858
                DOI: 10.1038/nm.3445
                PMC ID: 3959167
                PubMed ID: 24412925
                SO-VID: fe49f679-6fa1-4fd9-b7a4-2a58158bc64d
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                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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