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ilar to what has already been shown for expansion within the bulk CD8+ compartment10).
Memory is the hallmark of adaptive immunity; indeed, antigen-driven clonal expansion of effector T cells may generate antigen-specific lymphocytes that may persist life long (reviewed by Sallusto et al.18). These cells, which are known as memory cells, confer immediate and effec- tive protection against pathogens upon antigen rechal- lenging; indeed, memory immune cells are selected for their higher affinity for cognate antigens, and rapidly acti- vate from their resting state after antigen stimulation.18 Among T cells, three subtypes of memory cells have been described:18 i) TEM, that carry the protective memory because of their ability to deliver effector functions; ii) central memory T cells (TCM), that home to secondary lymphoid organs and exert reactive memory through their cross-differentiation toward TEM and effector T cells (TEFF); and iii) memory stem T cells (TSCM), which have been described as a less differentiated subset that has bet- ter self-renewal and the ability to differentiate into dis- tinct subsets of memory T cells. Only limited data are available about memory T cells in AA. In 2009, Hu et al. reported that TEM and TEMRA (a further subset of terminally differentiated TEM characterized by CD45RA expression and by better effector function) are increased in CD4+ and CD8+ T-cell subsets in AA patients, while naïve T cells are decreased.19 More recently, the US National Institutes of Health group has described that even TSCM
are increased in circulating CD8+ T cells of AA patients.20 However, while these observations depict the broad immune derangement which is expected in an autoim- mune disease such as AA, they do not provide any clues about the pathogenic role of these cells. In contrast, the demonstration of clonality within the TEM compartment shown by Giudice et al. seems pathogenically more rele- vant, according to the scenario depicted in Figure 1. Indeed, a clonal immune response specific for (or cross- reactive with) HSC can be elicited by unknown antigens or triggers, eventually causing some impairment of hematopoiesis. If these clonal TEFF do not undergo apop- tosis (as usually occurrs in a physiological immune response), they may lead to overt AA.1 Given the plas- ticity of T cells, some of these clonal, antigen-specific cells may eventually acquire a TEM or a TCM functional phenotype, generating some skewing within the broad TEM repertoire, as found by Giudice et al.2 The presence of these clonal (possibly HSC-specific) TEM would account for continuous damage to the hematopoiesis, since in the presence of persistent antigen spread they may serve as a reservoir for newly-generated TEFF. Thus, irrespective of the regulatory role postulated by Giudice et al.,2 the pres- ence of clonal TEM would represent the signature of a deeper immune derangement, possibly associated with a dismal clinical outcome.
In conclusion, the availability of high-throughput tech- nologies is providing biomarkers which anticipate future
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Figure 1. T-cell clonality in aplastic anemia. Unknown antigens and triggers may elicit a clonal immune response specific for (or cross-reactive with) hematopoietic stem cells (HSC). These clonal, activated T cells tend to expand delivering their immune damage over hematopoiesis. At the same time, some of these clonally expanded activated T cells may acquire an effector memory T cell (TEM) functional phenotype, leading to skewing of the TEM cell repertoire. While activated effector T cells (TEFF) may undergo anergy or apoptosis (even as a consequence of immunosuppressive therapies), TEM represent a continuous reservoir for HSC-specific T cells, which may exert their effector function upon rechallenging with the antigen. (This is very likely, given the typical antigen spread seen in autoimmune diseases.) Thus, the presence of clonal TEM, which likely share the same antigen-specificity with large TEFF clones found in bulk CD8+ populations, represent a biomarker of a deep-root- ed immune derangement, possibly associated with a dismal disease course.
haematologica | 2018; 103(5)