Adult T Cell Leukemia/Lymphoma: FoxP3+ Cells and the Cell-Mediated Immune Response to HTLV-1
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).
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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 PathologyCitation 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 VirologyCitation 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].
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