In this issue: Eur. J. Immunol. 7'12

Cover image


The cover image shows immunohistochemical analysis of HLA class I expression on primary cutaneous melanomas, with HLA class I stained in blue and the nuclear melanoma marker MITF (microftalmia associated transcription factor) stained in brown. The image is taken from Balsamo et al. (pp. 1834–1843) in which the authors show that in vivo levels of NK-cell infiltration in tumors are below those determined in vitro to be required for efficient tumor-cell killing. Furthermore, at these low NK cell levels, the tumor cells develop resistance in vitro to NK-cell killing by increasing expression of classical and nonclassical HLA class I molecules, a process that is dependent on NK-mediated IFN-γ release.

Immunoglobulin A: Potent therapeutic antibodies to treat cancer?


IgA is commonly recognized as the dominant antibody at mucosal sites with the important passive defensive function of shielding mucosal surfaces from invading pathogens. However, it is less well known that IgA can potently stimulate and activate neutrophils through interaction with their Fc receptor, FcαRI. Neutrophils have previously been identified as potential effector cells for monoclonal antibody (mAb) therapy of cancer. In this issue, Otten et al. demonstrate that targeting FcαRI with IgA leads to the rapid migration of neutrophils into, and destruction of, tumor colonies. Moreover, reciprocal communication between neutrophils and endothelial cells is shown, which is important as neutrophils need to extravasate from the circulation in order to target tumors. Neither neutrophil migration nor cross-talk with endothelial cells was observed when IgG mAbs were used. Thus, taking into account IgA's neutrophil recruiting capacity, the authors anticipate that IgA may represent a prominent component of future therapeutic mAb strategies in cancer treatment.

Abacavir hypersensitivity: Unraveling the mechanism of T-cell stimulation by drugs


Drug hypersensitivity is caused by immune responses to drugs; however, the underlying molecular mechanisms leading to T-cell activation remain a matter of debate. The hapten theory postulates covalent binding between drugs and proteins, eventually resulting in the presentation of drug-modified peptides on MHC molecules. However, non-covalent pharmacological drug interactions may occur within the MHC-(peptide)-TCR complex (p-i concept), leading to drug-specific T-cell activation in the absence of classical antigen presentation mechanisms.

In this issue, Adam et al. investigate HLA-B*5701-restricted T-cell activation by abacavir, a drug used for HIV treatment, causing hypersensitivity in 50% of HLA-B*5701+ patients. T-cell reactivity to abacavir occurred immediately upon drug encounter and was shown to bypass the proteasome, excluding the MHC class I processing machinery. Moreover, the T-cell activation kinetic was dependent on the TCR avidity and was shaped by antigen availability. Overall, this suggests a direct, non-covalent abacavir interaction with HLA-B*5701, leading to the activation of T cells.

A new lineage of human CD4+ memory T cells


While CD25 expression is restricted primarily to CD4+Foxp3POS Treg cells in mice, a large proportion of CD4+FOXP3NEG non-Treg cells have been reported to express low-to-intermediate levels of CD25 in humans. Earlier studies have suggested that this CD25LO/INTFOXP3NEG population represents recently activated T cells. In this issue, Triplett et al. show that the CD4+CD25INTFOXP3NEG T cells from human PBMCs are not recently activated, but represent a quiescent memory population that includes the majority of memory CD4+ T cells (∼75%) in humans. Furthermore, the authors show that the CD4+CD25INTFOXP3NEG memory population is functionally distinct from other CD4+ T cells and is uniquely affected by IL-2 treatment in cancer patients. The CD25NEG memory population contains late-differentiated effector-like T cells, while the CD25INT population resembles central memory cells. These findings shed new light on the role of this novel CD4+CD25INTFOXP3NEG T-cell population in humans and may have important clinical implications for therapies that target IL-2 and CD25.

Cell-specific promoters contribute to the regulation of ST2 and IL-33


ST2 is the signaling receptor for the inflammatory cytokine IL-33, and also exists as a soluble decoy receptor expressed by fibro-blasts. Earlier work identified two promoters driving ST2 expression in different cell types. In this issue, Lipsky et al. describe the results of a study in which they selectively deleted the more proximal of the two ST2 promoters. They found that the proximal promoter is crucial for fibroblast expression of both forms of ST2 and that fibroblast responsiveness to IL-33 depends on this promoter. In contrast, the second promoter is important for the expression of the signaling form of ST2 on mast cells. Interestingly, complete loss of the proximal promoter affected neither mast cell responses to IL-33 nor production of soluble ST2 in vivo. The authors conclude that this model is useful for studying the regulation of the IL-33–ST2 axis and that future studies in different physiologic contexts are warranted.

Circulating immunosuppressive exosomes facilitate tumor immune evasion


Despite the expression of immunogenic tumor-specific antigens, tumor cells are equipped with multiple mechanisms to escape the host's immune surveillance. Suppression of tumor antigen-specific immune responses is usually seen during tumor progression. In this issue, Yang et al. demonstrate that circulating exosomes, which are endosomal-derived membrane vesicles with immunomodulatory abilities, confer immunosuppression. Exosomes isolated from the blood plasma of mice bearing tumors expressing OVA as a model tumor antigen effectively suppressed an OVA-specific inflammatory response, suggesting that immunosuppressive exosomes capable of downregulating tumor antigen-specific immune responses are present in the blood circulation of tumor-bearing hosts. Most tumor and hematopoietic cell types secrete exosomes. Interestingly, the authors demonstrate that tumor-derived exosomes are not highly enriched in exosomes isolated from the blood plasma of mice bearing subcutaneous melanoma. Instead, the antigen-specific immunosuppressive effect is predominantly conferred by host-derived MHC class II+ exosomes, presumably derived from antigen-presenting cells.