Reduced NFAT1 Protein Expression in Human Umbilical Cord Blood T Lymphocytes

Abstract

Umbilical cord blood (UCB) stem cells from related and unrelated allogeneic donors have emerged as novel treatment for patients with hematologic malignancies. The incidence and severity of acute graft-versus-host disease (GVHD) after UCB transplantation compares favorably with that observed in recipients of matched unrelated donor allogeneic grafts, but remains a major cause of morbidity and mortality. It has been shown that stimulated lymphocytes from UCB have reduced production of cytokines including interferon-γ (IFN-γ) and tumor necrosis factor- (TNF-), which play a role in GVHD pathophysiology. We investigated the molecular mechanisms underlying this reduced cytokine production by analyzing expression of nuclear factor of activated T cells-1 (NFAT1) in UCB T cells. We detected no constitutive expression of NFAT1 protein in unstimulated UCB T cells compared with adult T cells. Moreover, although NFAT1 expression in UCB T cells was upregulated after prolonged (40 hours) T-cell stimulation, it was only partially upregulated when compared with adult controls. Our observation of minimal NFAT1 expression after stimulation correlated with reduced cytoplasmic IFN-γ and TNF- production in UCB T cells studied simultaneously. Reduced NFAT1 expression may blunt amplification of donor UCB T-cell alloresponsiveness against recipient antigens, thereby potentially limiting GVHD incidence and severity after allogeneic UCB transplantation.

Cord blood–derived T cells allow the generation of a more naïve tumor‐reactive cytotoxic T‐cell phenotype

“…[38][39][40] NFAT promotes PD-1 expression in early activated CD81 T cells in adults; therefore, unbalanced NFAT signaling may contribute to T-cell anergy. 16,41 Interestingly, our activated CD81 CB T cells did not express PD-1, maybe due to impaired NFAT signaling, but this should be analyzed in the future. Wei and colleagues 42 demonstrated that various T-cell effector functions show differential susceptibility to PD-1 signaling and that already low levels of PD-1 can inhibit T-cell expansion as well as IL-2 and TNFa production.…”

“…[10][11][12][13][14] Furthermore, CB T cells are characterized by impaired nuclear factor of activated T cells (NFAT) signaling and reduced reactivity. [15][16][17] Further investigation is needed to gain a thorough understanding of the na€ ıvet e of CB immune cells and the interplay with recipient target T cells in the context of GVHD and GVT effects.…”

“…[10][11][12][13][14] Furthermore, CB T cells are characterized by impaired nuclear factor of activated T cells (NFAT) signaling and reduced reactivity. [15][16][17] Further investigation is needed to gain a thorough understanding of the na€ ıvet e of CB immune cells and the interplay with recipient target T cells in the context of GVHD and GVT effects.Studies reporting the successful stimulation and activation of antigen-specific CD41 T-helper and cytotoxic CD81 T lymphocytes (CTLs) from CB using autologous lymphoblastoid cell lines (LCLs) 18 or CB-derived DCs for antigen presentation 19 are scarce. One group recently reported the generation of multivirus-specific CB CTLs using a combination of LCLs and DCs 20 and adoptive transfer of multivirus-specific T cells resulted in both virus-free survival and complete remission in patients.…”

T cell-mediated immune responses in human newborns: ready to learn?

“…Contain high concentrations of TRECs [10,11] High cell turn-over [10][11][12][13][14] Have high constitutive telomerase activity and long telomeric sequences [10] Have increased susceptibility to apoptosis, prevented by cytokines signalling through the IL-2 receptor g -chain [11,14,16] Proliferation induced by IL-7 and IL-15 [10,11,13,14,16,17,19,20] Low production of IFN-g by CD4 T lymphocytes associated with hypermethylation of IFN-g promoter [25,26,28] Expression of CD40 ligand by CD4 T lymphocytes is controversial [29][30][31][32][33][34][35] Expression of NFAT by CD4 T lymphocytes is controversial [36][37][38] CD25 + regulatory T lymphocytes occur spontaneously during foetal life [41][42][43][44] and previously been proposed as a marker of recent thymic emigrants [40]. Essential regulatory mechanisms controlling T cell responses are in place in early life.…”

Interleukin 10, produced in abundance by human newborn T cells, may be the regulator of increased tolerance associated with cord blood stem cell transplantation

“…These studies have been echoed by studies in the human neonate that demonstrated a predisposition towards Th2 cytokine production in response to stimulation with allergens (Prescott et al, 1998). Recently, absence of expression of nuclear factor of activated T-cell transcription factor (NFAT)-1, a critical regulator of cytokine gene expression, in human cord blood T cells has been considered as a basis for diminished GVHD (Kadereit et al, 1999). Thus, the elucidation of the role of constitutive cytokine production by cord blood compared with adult-derived T cells in the mediation of GVHD remains an important goal in stem cell transplantation immunology.…”