There’s no such fool like an immunosenescent fool

In this issue of Blood, Stepensky et al provide an astute description of immunosenescence arising from deficiency in tripeptidyl peptidase II (TPPII).¹  Senescence of T and B lymphocytes is a striking finding, which has recently come into the limelight because it can be linked to primary immunodeficiency syndromes with autoimmunity.

Immune dysregulation and autoimmunity are being recognized as features of a growing number of primary immunodeficiency (PID) diseases that often add to an impaired capacity to fend off infections. Symptoms arising from autoimmunity, however, may also present as the first or only sign of PID. It is counterintuitive why an aging immune system fails in both self-defense and self-recognition: it is less capable of fighting infections, responding to vaccines, or eliminating tumor cells but more prone to the development of autoimmune conditions, such as rheumatoid arthritis (reviewed in Goronzy et al² ). Altered homeostasis results in age-associated changes within the lymphocyte repertoire; these are detectable and occur prematurely in states of autoimmunity.²  The cellular changes in rheumatologic autoimmune diseases appear to be associated with telomere erosion and thus with replicative senescence.²  This is in contrast to the stress-induced or “acute” senescence which is proposed to occur in TPPII deficiency. However, shared features include an increased proportion of terminally differentiated effector memory T cells, loss of naivety, a contracted antigen receptor repertoire, deregulated apoptosis, and impaired lymphocyte proliferation.¹  Physiologic induction of cell-cycle arrest, senescence, or apoptosis is an evolutionarily conserved cell fate decision. This is executed in response to various stresses in a manner dependent on the tissue type as well as the kind and degree of stress. In the pathological context of TPPII deficiency, the lymphocyte repertoire is skewed toward terminally differentiated and senescent phenotypes. This may result from both an impaired stress response per se and abrogated processing of peptides, which are not (further) degraded by the proteasome, such as cytotoxic T lymphocyte antigens and epitope precursors required for presentation by major histocompatibility complex class I.³  The surviving “end-stage” lymphocytes not only are inefficient to combat infections but also appear to have been selected for autoreactive clones! It remains to be elucidated whether cellular senescence in the context of TPPII deficiency is a direct and cell-intrinsic event and how its molecular mechanism relates to similar immunosenescence phenotypes observed in recently discovered primary immunodeficiencies associated with immune cytopenia, eg, as deficiency of the vesicle-trafficking– and autophagy-linked lipopolysaccharide-responsive beige and anchor-containing (LRBA) protein, haploinsufficiency of cytotoxic T-lymphocyte antigen 4 (CTLA4), gain of function of phosphatidylinositol-3-OH kinase (PI(3)K) p110delta or loss of PI(3)K p85alpha, or deficiency of serine threonine kinase 4 (STK4; see figure).^4-7  Recently, a senescence-like disturbance of T-cell development was also reported in the paramount example of autoimmune cytopenia in PID, ie, autoimmune lymphoproliferative syndrome (ALPS) due to Fas deficiency.⁸  It is not clear if immunosenescence serves as a sufficient cause of autoimmune cytopenia. An array of mechanisms which are not linked to immunosenescence may contribute to the cytopenia in PID. These include a tipped balance between TH17 and regulatory T cells, most recently reported in gain-of-function mutations of signal transducer and activator of transcription 3,⁹  several syndromes of immune dysregulation and hemophagocytosis, syndromes of bone marrow failure, and secondary myelosuppression (reviewed in Seidel¹⁰ ). Thus, detection of markers of immunosenescence should be considered a valuable tool that, in addition to the determination of naive T cells, will support the immune phenotypic differential diagnosis. Although not routine, this should be feasible in many laboratories. When done in suspected PID, it should be of particular interest in the context of autoimmune cytopenias of childhood. A pertinent catalog of diseases will also pave the way to clarifying the signaling pathways that underlie immunosenescence and autoimmune cytopenia. The figure provides a sketch of candidate pathways that may be targeted by small compounds or antibodies. It is safe to assume that eventually, patients with chronic immune cytopenias will be the beneficiaries of these investigations.