Adult T Cell Leukemia/Lymphoma: FoxP3+ Cells and the Cell-Mediated Immune Response to HTLV-1

https://doi.org/10.1016/B978-0-12-385524-4.00004-0Get rights and content

Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukaemia/lymphoma (ATLL) in ∼5% of HTLV-1-infected people. ATLL cells frequently express several molecules that are characteristic of regulatory T cells (Tregs), notably CD4, CD25 and the transcription factor FoxP3. It has therefore recently been suggested that HTLV-1 selectively infects and transforms Tregs. We show that HTLV-1 induces and maintains a high frequency of FoxP3+ T cells by inducing expression of the chemokine CCL22; the frequency is especially high in patients with chronic ATLL. In turn, the FoxP3+ T cells exert both potentially beneficial and harmful effects: they suppress the growth of autologous ATLL clones and may also suppress the host's cytotoxic T lymphocyte response, which normally limits HTLV-1 replication and reduces the risk of HTLV-1-associated diseases. Although ATLL cells may exert immune suppressive effects, we conclude that ATLL is not necessarily a tumour of classical FoxP3+ Tregs.

Introduction

Human T-lymphotropic virus Type 1 (HTLV-1) was first known as human T cell leukemia virus, because it causes an aggressive malignancy as CD4+ T cells called adult T cell leukemia/lymphoma (ATLL) (Uchiyama et al., 1977). In the 1980s, HTLV-1 infection was discovered to be associated with a chronic inflammatory disease of the central nervous system, tropical spastic paraparesis (TSP): the syndrome is now called HTLV-1-associated myelopathy (HAM) or HAM/TSP. Subsequently, HTLV-1 infection has also been associated with cases of polymyositis (Morgan et al., 1989), uveitis (Mochizuki et al., 1992), and arthritis (Nishioka et al., 1989). HTLV-1 infection is widespread (Mueller and Blattner, 1997) in the tropics and certain subtropical regions, notably southern Japan. The total number of people infected is very uncertain, because systematic epidemiological studies have not been made in many areas where HTLV-1 is known or suspected to be endemic (de The and Bomford, 1993, Hlela et al., 2009). Certain foci of high endemicity are known, such as southern Kyushu and Okinawa in Japan, where between 8% and 20% of adults are seropositive for the virus.

Section snippets

Adult T cell leukemia/lymphoma

HTLV-1 was first isolated from a patient with a cutaneous T-cell malignancy (Poiesz et al., 1980). Because of similarities to ATLL in both the clinical picture and the abnormal T-cell morphology, it later became clear that HTLV-1 was identical to the causative agent of ATLL, first known as ATLV in Japan (Blattner et al., 1982, Hinuma et al., 1981, Hinuma et al., 1982, Yoshida et al., 1982, Yoshida et al., 1984).

ATLL presents clinically with lymphadenopathy and hepatosplenomegaly; skin

Cellular immune response to HTLV-1

There is now compelling evidence that the CD8+ T-cell response to HTLV-1 is a major determinant, perhaps the chief single determinant, of the outcome of HTLV-1 infection. The most important single line of evidence for this statement is the observation that certain HLA Class 1 alleles were associated with a lower prevalence of HAM/TSP and a lower proviral load in southern Japan (Bangham, 2008, Jeffery et al., 1999, Jeffery et al., 2000). The evidence for the role of CTLs in HTLV-1 infection has

FOXP3 and regulatory T cells

Certain T-cell subsets known as regulatory T cells (Tregs) are capable of suppressing antigen-specific responses by effector T cells (Sakaguchi et al., 2006). The best single marker of the main population of Tregs currently known is the forkhead transcription factor FoxP3 (Ziegler, 2006). However, not all FoxP3+ cells are Tregs: T-cell activation causes transient FoxP3 expression in the human, and this transient expression of FoxP3 is not accompanied by Treg functions (Allan et al., 2007, Wang

Conclusions

The work summarized above suggests the following conclusions (Fig. 6):

  • (1)

    HTLV-1 Tax protein induces CCL22 production by infected CD4+ T cells (Hieshima et al., 2008, Toulza et al., 2010, Yoshie et al., 2002). In turn, the CCL22 maintains the survival of an abnormally high frequency of FoxP3+ cells in the circulation in HTLV-1-positive individuals.

  • (2)

    HTLV-1 Tax protein is also associated with FoxP3 expression inside the infected cell itself (Toulza et al., 2008, Toulza et al., 2009, Toulza et al., 2010

Acknowledgments

The authors thank Graham Taylor and colleagues in the laboratory for critical discussion and the volunteers in the clinic for providing samples. This work was supported by the Wellcome Trust UK and funding under the Sixth Research Framework Programme of the European Union, Project INCA (LSHC-CT-2005-018704).

References (81)

  • J. Nilsson et al.

    HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS

    Blood

    (2006)
  • K. Nishioka et al.

    Chronic inflammatory arthropathy associated with HTLV-I

    Lancet

    (1989)
  • S. Shiratori et al.

    A retrospective analysis of allogeneic hematopoietic stem cell transplantation for adult T cell leukemia/lymphoma (ATL): Clinical impact of graft-versus-leukemia/lymphoma effect

    Biol. Blood Marrow Transplant.

    (2008)
  • F. Toulza et al.

    High frequency of CD4+FoxP3+ cells in HTLV-1 infection: inverse correlation with HTLV-1-specific CTL response

    Blood

    (2008)
  • K. Tsukasaki et al.

    Integration patterns of HTLV-I provirus in relation to the clinical course of ATL: Frequent clonal change at crisis from indolent disease

    Blood

    (1997)
  • T. Uchiyama et al.

    Adult T-cell leukemia: Clinical and hematologic features of 16 cases

    Blood

    (1977)
  • K. Yamaguchi et al.

    A proposal for smoldering adult T-cell leukemia: A clinicopathologic study of five cases

    Blood

    (1983)
  • O. Yoshie et al.

    Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells

    Blood

    (2002)
  • S.E. Allan et al.

    Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production

    Int. Immunol.

    (2007)
  • J. Andersson et al.

    The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients

    J. Immunol.

    (2005)
  • B. Asquith et al.

    A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in human T-lymphotropic virus type 1 proviral load

    J. Gen. Virol.

    (2005)
  • C.R.M. Bangham

    Human T-lymphotropic virus type 1 (HTLV-1)-associated diseases

  • C.R.M. Bangham

    CTL quality and the control of human retroviral infections

    Eur. J. Immunol.

    (2009)
  • C.R.M. Bangham et al.

    The immune control of HTLV-1 infection: Selection forces and dynamics

    Front. Biosci.

    (2009)
  • A. Bazarbachi et al.

    Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes

    J. Clin. Oncol.

    (2010)
  • I. Best et al.

    IFN-gamma production in response to Tax 161-233, and frequency of CD4+ Foxp3+ and Lin HLA-DRhigh CD123+ cells, discriminate HAM/TSP patients from asymptomatic HTLV-1-carriers in a Peruvian population

    Immunology

    (2009)
  • Y. Belkaid et al.

    Natural regulatory T cells in infectious disease

    Nat. Immunol.

    (2005)
  • W.A. Blattner et al.

    The human type-C retrovirus, HTLV, in Blacks from the Caribbean region, and relationship to adult T-cell leukemia/lymphoma

    Int. J. Cancer

    (1982)
  • M. Boxus et al.

    Mechanisms of HTLV-1 persistence and transformation

    Br. J. Cancer

    (2009)
  • Y. Cao et al.

    Local accumulation of FOXP3+ regulatory T cells: Evidence for an immune evasion mechanism in patients with large condylomata acuminata

    J. Immunol.

    (2008)
  • S. Chen et al.

    Regulatory T cell-like activity of Foxp31 adult T cell leukemia cells

    Int. Immunol.

    (2006)
  • F.R. Cleghorn et al.

    Effect of human T-lymphotropic virus type I infection on non-Hodgkin's lymphoma incidence

    J. Natl. Cancer Inst.

    (1995)
  • G. de The et al.

    An HTLV-I vaccine: Why, how, for whom? AIDS Res

    Hum. Retroviruses

    (1993)
  • J. Fan et al.

    APOBEC3G generates nonsense mutations in human T-cell leukemia virus type 1 proviral genomes in vivo

    J. Virol.

    (2010)
  • A. Gallimore et al.

    Regulatory T cells and tumour immunity—Observations in mice and men

    Immunology

    (2008)
  • G. Gaudray et al.

    The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription

    J. Virol.

    (2002)
  • R. Grassmann et al.

    Molecular mechanisms of cellular transformation by HTLV-1 Tax

    Oncogene

    (2005)
  • K. Hieshima et al.

    Tax-inducible production of CC chemokine ligand 22 by human T cell leukemia virus type 1 (HTLV-1)-infected T cells promotes preferential transmission of HTLV-1 to CCR4-expressing CD4+ T cells

    J. Immunol.

    (2008)
  • S. Hilburn et al.

    In vivo expression of HTLV-1 basic leucine-zipper protein generates specific CD8+ and CD4+ T-lymphocyte responses that correlate with clinical outcome

    J. Infect. Dis.

    (2011)
  • Y. Hinuma et al.

    Antibodies to adult T-cell leukemia-virus-associated antigen (ATLA) in sera from patients with ATL and controls in Japan: A nation-wide sero-epidemiologic study

    Int. J. Cancer

    (1982)
  • Cited by (25)

    • FOXP3-positive T-cell lymphomas in non-HTLV1 carriers include ALK-negative anaplastic large cell lymphoma: expanding the spectrum of T-cell lymphomas with regulatory phenotype

      2018, Human Pathology
      Citation Excerpt :

      ATLL is postulated to arise from Treg cells and recapitulates a CD4 + CD25+ FOXP3+ phenotype in addition to its typical association with HTLV-1 [1,7,8,15-18]. Although the expression of FOXP3 has been considerate a specific marker for normal Tregs, its expression on ATLL is not uniform [7,8,16-18], and ranges from 36% to 68% in the lymphomatous variant of ATLL and a higher level of expression in chronic ATLL [16,17,26]. The heterogeneity of FOXP3 expression in ATLL cases may reflects in part the heterogeneity of ATLL in its different clinic-pathological presentations [17].

    • How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)?

      2015, Current Opinion in Virology
      Citation Excerpt :

      However, in HTLV-1-infected Tregs the expression and actions of FoxP3 in the infected cell are impaired by the products of the tax [38] and HBZ [39] genes, and HTLV-1-infected FoxP3+ cells do not themselves exert regulatory functions [37]. We conclude that, although ATL may arise in a Treg clone, ATL is not necessarily a malignancy of Tregs [40,41]. Both Tax and HBZ are implicated in oncogenesis [42].

    • Biology and molecular pathogenesis of mature t-cell lymphomas

      2021, Cold Spring Harbor Perspectives in Medicine
    View all citing articles on Scopus
    View full text