Decrease of memory T helper cells (CD4+ CD45R0+) in hairy cell leukemia.

Patients with hairy cell leukemia (HCL) are prone to opportunistic infections, which suggests an impaired T-cell functioning. To investigate a possible mechanism of such an impairment, we determined the numbers of naive and memory T cells by measuring the expression of CD45R0 on CD4+ and CD8+ T cells in 23 HCL patients. As control, 13 healthy subjects and 13 patients with other chronic B-cell leukemias were studied. In HCL patients with active disease, the percentage of CD4+ CD45R0+ T cells was significantly lower compared to healthy subjects (41% versus 57%, p = 0.01). Also the absolute numbers of CD4+ CD45R0+ T cells were reduced (396 x 10(6)/l versus 615 x 10(6)/l, p = 0.02) compared to healthy subjects, whereas within the CD8+ subset no differences were found. A contrasting elevation of percentages and numbers of CD45R0-expressing T cells (p < 0.0001) was seen in patients with chronic lymphocytic leukemia or leukemic non-Hodgkin's lymphoma. No relationship between CD4+ CD45R0+ and splenectomy, treatment with alpha-interferon or monocyte numbers was found in the HCL population. Despite the fact that the underlying mechanism of the reduced expression of CD45R0 in CD4+ T cells remains unclear, our observations may contribute to the understanding of an impaired T-cell functioning in HCL.

CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor.

Expression of CD200, the gene encoding the ligand for the inhibitory immune receptor CD200R, is an independent prognostic factor for various forms of leukemia predicting worse overall survival of the patients. The enhanced expression of CD200 on the tumors implies that anti-tumor responses can be enhanced by blockage of the CD200-CD200R interaction. Indeed, antibody-mediated blockade of the CD200-CD200R inhibitory axis is currently evaluated in clinical tests to boost immune responses against CD200-expressing tumors. Here, we show that mice lacking CD200, the exclusive ligand for CD200R, are resistant to chemical skin carcinogenesis. Importantly, CD200R controls tumor outgrowth independently of CD200 expression by the tumor cells themselves. Furthermore, Cd200(-/-) mice do not become tolerant to intranasally administered antigens, suggesting that tumor rejection is normally suppressed through CD200-induced immune tolerance. Decreased tumor outgrowth is accompanied by increased expression of the proinflammatory cytokines interleukin (IL)-1ß and IL-6 by the lymph node (LN) dendritic cells. During carcinogenesis, skin-draining LNs of Cd200(-/-) mice contain increased numbers of IL-17-producing FoxP3(+) cells, which preferentially home to the tumors. Thus, the CD200-CD200R axis induces tolerance to external and tumor antigens and influences the T-regulatory/Th17 cell ratio. We demonstrate for the first time that the absence of CD200R signaling inhibits outgrowth of an endogenous tumor irrespective of CD200 expression by the tumor cells. This important paradigm shift leads to a much broader applicability of CD200-blockade in the treatment of tumors.

Intrinsic genetic instability of normal human lymphocytes and its implication for loss of heterozygosity.

A combination of flow cytometry and microsatellite analysis was used to investigate loss of expression of HLA-A and/or HLA-B alleles and concurrent LOH at polymorphic chromosome 6 loci both in freshly isolated lymphocytes (in vivo mutations) and in lymphocytes cultured ex vivo. The fraction of in vivo mutants that showed LOH at 6p appeared to vary from 0%-49% for various donors. During culturing ex vivo, HLA-A(-) cells arose at a high rate and showed simultaneous loss of expression at the linked HLA-B locus. Up to 90% of the ex vivo arisen HLA-A2(-) cell population showed LOH of multiple 6p markers, and 50% had lost heterozygosity at 6q. This ex vivo spectrum resembles that found in HLA-A2 mutants obtained from lymphoblastoid cells. The HLA-A2 mutants present in vivo may reflect only a small fraction of the mutants that can be detected ex vivo. In normal lymphocytes, in vivo only mitotic recombination appears to be sustained, indicating the importance of this mechanism for tumor initiation in normal cells. Although mutations resulting in LOH at both chromosome 6 arms were shown to result in nonviable cells in normal lymphocytes, they have been shown to result in viable mutants in lymphoblastoid cells. We hypothesize that these types of mutations also occur in vivo but only survive in cells that already harbor a mutated genetic background. In light of the high rate at which these types of mutations occur, they may contribute to cancer progression.