TY - JOUR
T1 - Early effects of htlv-1 infection on the activation, exhaustion, and differentiation of t-cells in humanized nsg mice
AU - Espíndola, Otávio de Melo
AU - Rijnstra, Esther Siteur-Van
AU - Frankin, Esmay
AU - Weijer, Kees
AU - van der Velden, Yme Ubeles
AU - Berkhout, Ben
AU - Blom, Bianca
AU - Villaudy, Julien
N1 - Funding Information: Funding: This research was funded by the Oswaldo Cruz Foundation (FIOCRUZ), Brazil. O.d.M.E. was a recipient of a post-doctorate fellowship by the Science without Borders Program of the Brazilian National Council for Scientific and Technological Development (CNPq) (grant no. 249958/2013-9). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4+ T-cells associated with HTLV-1 infection. In this study, we used the model of immunodeficient NSG mice reconstituted with a functional human immune system (HIS) to investigate early events in HTLV-1 pathogenesis. Upon infection, human T-cells rapidly increased in the blood and lymphoid tissues, particularly CD4+CD25+ T-cells. Proliferation of CD4+ T-cells in the spleen and mesenteric lymph nodes (MLN) correlated with HTLV-1 proviral load and CD25 expression. In addition, splenomegaly, a common feature of ATLL in humans, was also observed. CD4+ and CD8+ T-cells predominantly displayed an effector memory phenotype (CD45RA−CCR7−) and expressed CXCR3 and CCR5 chemokine receptors, suggesting the polarization into a Th1 phenotype. Activated CD8+ T-cells expressed granzyme B and perforin; however, the interferon-γ response by these cells was limited, possibly due to elevated PD-1 expression and increased frequency of CD4+FoxP3+ regulatory T-cells in MLN. Thus, HTLV-1-infected HIS-NSG mice reproduced several characteristics of infection in humans, and it may be helpful to investigate ATLL-related events and to perform preclinical studies. Moreover, aspects of chronic infection were already present at early stages in this experimental model. Collectively, we suggest that HTLV-1 infection modulates host immune responses to favor viral persistence.
AB - Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4+ T-cells associated with HTLV-1 infection. In this study, we used the model of immunodeficient NSG mice reconstituted with a functional human immune system (HIS) to investigate early events in HTLV-1 pathogenesis. Upon infection, human T-cells rapidly increased in the blood and lymphoid tissues, particularly CD4+CD25+ T-cells. Proliferation of CD4+ T-cells in the spleen and mesenteric lymph nodes (MLN) correlated with HTLV-1 proviral load and CD25 expression. In addition, splenomegaly, a common feature of ATLL in humans, was also observed. CD4+ and CD8+ T-cells predominantly displayed an effector memory phenotype (CD45RA−CCR7−) and expressed CXCR3 and CCR5 chemokine receptors, suggesting the polarization into a Th1 phenotype. Activated CD8+ T-cells expressed granzyme B and perforin; however, the interferon-γ response by these cells was limited, possibly due to elevated PD-1 expression and increased frequency of CD4+FoxP3+ regulatory T-cells in MLN. Thus, HTLV-1-infected HIS-NSG mice reproduced several characteristics of infection in humans, and it may be helpful to investigate ATLL-related events and to perform preclinical studies. Moreover, aspects of chronic infection were already present at early stages in this experimental model. Collectively, we suggest that HTLV-1 infection modulates host immune responses to favor viral persistence.
KW - ATLL
KW - Chemokine receptors
KW - Exhaustion
KW - HTLV-1
KW - Humanized mice
KW - NSG mice
KW - T-cells
UR - http://www.scopus.com/inward/record.url?scp=85115397443&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells10102514
DO - https://doi.org/10.3390/cells10102514
M3 - Article
C2 - 34685494
SN - 2073-4409
VL - 10
JO - Cells
JF - Cells
IS - 10
M1 - 2514
ER -