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T-Cell Abnormalities in Common Variable Immunodeficiency

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JCP Online First, published on May 6, 2016 as 10.1136/jclinpath-2015-203351 Review T-cell abnormalities in common variable J Clin Pathol: first published as 10.1136/jclinpath-2015-203351 on 6 May 2016. Downloaded from immunodeficiency: the hidden defect Gabriel K Wong,1,2 Aarnoud P Huissoon1,2 1MRC Centre for Immune ABSTRACT T-CELLS EXHAUSTION Regulation, University of This review discusses how the T-cell compartment in In addition to the quantitative alterations in CD4 Birmingham, Birmingham, UK fi 2West Midlands Primary common variable immunode ciency is marked by the and CD8 T cells, abnormalities in cytokine produc- Immunodeficiency Centre, premature arrest in thymic output, leading to T-cell tion and cell proliferation have been reported in Birmingham Heartlands exhaustion and immune dysregulation. Although B CVID. Experimental data for cytokine output have Hospital, Birmingham, UK cells have been the main focus of the disorder, ample been well summarised by Varzaneh et al,7 where experimental data suggest that T-cell abnormalities sluggish production of interleukin (IL) 2 along with Correspondence to fi Dr Gabriel Wong, MRC Centre can be seen in a large proportion of Freiburg Group de ciencies in other cytokines such as IL-4, IL-5 7–9 for Immune Regulation, 1a patients and those suffering from inflammatory and IL-10 were reported by a number of studies. University of Birmingham, complications. The reductions in T-cell receptor On the contrary, high levels of inflammatory cyto- Medical School, Vincent Drive, excision circles, naïve T cells, invariant NKT cells and kines such as IL-6, interferon (IFN)-γ and tumour Edgbaston, Birmingham B15 α 7 2TT, UK; [email protected] regulatory T cells suggest a diminished thymic output, necrosis factor (TNF)- were observed. During while CD8 T cells are driven towards exhaustion the acute phase of a viral infection in immunocom- Received 17 December 2015 either via an antigen-dependent or an antigen- petent individuals, elevations in the classical trio of Revised 13 March 2016 independent manner. The theoretical risk of anti-T-cell IL-2, IFNγ and TNFα are typically observed. By Accepted 22 March 2016 therapies is discussed, highlighting the need for an contrast, studies in chronic hepatitis C and HIV international effort in generating longitudinal data in infections demonstrated that T-cell exhaustion, by addition to better-defined underlying molecular phenotypic and functional alterations, following a characterisation. long period of antigenic stimulation was typically marked by the sequential disappearance of IL-2 and then TNFα.10 11 Therefore, the cytokine signa- Common variable immunodeficiency (CVID) is a ture in CVID mimics an earlier phase of T-cell heterogeneous and enigmatic primary immunodefi- exhaustion. ciency disorder marked by the failure of humoral Studies of T-cell proliferation also support the idea immunity and immune dysregulation. The discover- of a state of T-cell exhaustion. Earlier studies showed ies of T-cell-related molecular defects in hyper IgM that T-cell proliferation to phytohaemagglutinin and syndrome and Inducible T-cell costimulatory OKT3 was normal in patients with CVID but (ICOS) deficiency highlighted the negative conse- responses may be suboptimal against tetanus toxoid http://jcp.bmj.com/ quences to humoral immunity of the absence of or T-cell receptor (TCR) antibodies.12 Cyclic 12 T-cell support, and growing experimental data AMP-dependent protein kinase A type 1 (PKAI), an are now suggesting that the T-cell compartment is inhibitor of T-cell proliferation, can accumulate in also disrupted in patients with CVID. exhausted T cells following prolonged antigenic CD4 T-cell lymphopenia was first noted among stimulation.13 14 Using a PKAI selective antagonist, 3–5 patients with CVID and can dramatically reverse Aukrust et al15 demonstrated that normal prolifer- the normal CD4:8 ratio when combined with ation may be restored, suggesting that the poor T-cell on September 26, 2021 by guest. Protected copyright. expansion of senescent CD8 T cells, a feature not proliferation in CVID was secondary to senescence. 6 usually found in other antibody deficiencies. Programmed cell death protein 1 (PD-1), an Despite the array of observed in vitro T-cell abnor- extended family member of CD28 and Cytotoxic T- malities, the clinical hallmarks of a T-cell immuno- lymphocyte-associated protein 4 (CTLA-4), func- deficiency such as recurrent fungal and viral tions as an important immune checkpoint for T cells opportunistic infections are lacking in the majority and negatively regulates immune responses. In a of patients. murine lymphocytic choriomeningitis virus model, The heterogeneity of CVID and the progressive the synergistic use of IL-2 therapy and PD-1 block- change in its definition over the years make com- ade was able to reverse the exhausted immunophe- paring experimental data between studies difficult, notype of CD8 T cells and to regain control over but much can still be learnt. This article will the infection.16 Similar to the PKAI antagonist examine existing experimental data in the litera- experience, Perreau et al17 showed that in vitro CD4 ture regarding the role of T-cell defects in CVID proliferation in patients with CVID may also be and discuss how infection risk may increase pro- restored by blocking the programmed death ligand 1 gressively with decreasing thymic output, while and 2 axes (PD-L1/2). While anti-PD-1 antibodies the memory compartment shows evidence of have not been directly tested in CVID, clinical To cite: Wong GK, abnormal activation. Additionally, we will assess improvement was reported in patients who received Huissoon AP. J Clin Pathol fi 18 19 Published Online First: these ndings in the context of the revised 2014 IL-2 therapy in the past. Along with suboptimal [please include Day Month European Society for Immunodeficiencies (ESID) proliferation responses, a small number of studies Year] doi:10.1136/jclinpath- diagnostic criteria and discuss their therapeutic also suggest an impaired apoptotic function contrib- – 2015-203351 implications. uting to the accumulation of effete T cells.20 22 Wong GK, Huissoon AP. J Clin Pathol 2016;0:1–5. doi:10.1136/jclinpath-2015-203351 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd under licence. Review − Overall, both in vivo and in vitro data suggest the presence of inflammation in CVID is largely driven by CD3 innate lymph- J Clin Pathol: first published as 10.1136/jclinpath-2015-203351 on 6 May 2016. Downloaded from potentially reversible T-cell exhaustion in some patients with oid cells as opposed to T cells.40 CVID. Overall, chronic activation of CD8 T cells in CVID either via an antigen-dependent or antigen-independent manner is likely EXAGGERATED CD8 T-CELL RESPONSES to contribute to T-cell exhaustion. While CMV appears to be a While the cause of T-cell exhaustion in CVID is not clear, com- promising antigenic driver, the role of autoimmunity remains parable immunophenotypic features can be found with chronic unconfirmed and awaits further study. viral reactivation, raising the possibility of an antigenic driver. T cells of patients with CVID, in particular CD8 T cells, exhibit REDUCTION IN THYMIC OUTPUT high levels of activation and memory markers including CD29, Although current studies have not confirmed a putative anti- CD38, CD95, CD45RO and Human leukocyte antigen genic driver, the exaggerated T-cell response could also be due (HLA)-DR, and low expression of CD27, CD62L and to a lack of regulation. By peripheral blood immunophenotyp- – CD45RA.23 26 Although the expansion of T-cell memory is ing, Fevang et al were the first to demonstrate a lower frequency natural with advancing age, this process is greatly enhanced in of CD4+CD25+FOXP3+ T cells, an immunophenotype consid- CVID. Similarly, a disproportionate increase in terminally differ- ered characteristic of regulatory T cells (Treg), in patients with − entiated, senescent T cells (CCR7 CD45RA+) which are posi- CVID. RNA transcript levels for FOXP3 in CD4 T cells were tive for CD57 and PD-1 was found across multiple studies, also lower in patients, particularly in those with splenomegaly. further supporting the presence of a persistent, unregulated cel- To further support this, the frequency of Treg was inversely pro- lular immune response in CVID.6172627Unlike T-cell prolifer- portional to neopterin, a serum inflammatory protein.41 Several ation and cytokine output, immunophenotypic findings are studies had since confirmed the reduction in peripheral blood − more consistent across studies and affect a larger proportion of Tregs (CD4+CD25+FOXP3+ or CD4+CD25+CD127 ) with patients with inflammatory complications such as polyclonal the greatest deficiencies identified in patients with autoimmune – proliferation, chronic enteropathy, interstitial lung disease and cytopenias or Freiburg Group 1a.42 45 Carter et al46 also sug- autoimmunity. gested an association between decreased Tregs and CD8 T-cell To further support the presence of an underlying antigenic exhaustion in CVID. driver, CD8 T cells were shown to be oligoclonal by TCR Poor expressions of CTLA-4 and Glucocorticoid-induced – spectratyping.28 30 As normal repertoire diversity can be seen in TNFR-related protein (GITR) on Tregs were also noted, suggest- age-matched X-linked agammaglobulinaemia patients, this oligo- ing a functional deficit.46 47 Tregs isolated from patients with clonality was not thought to be secondary to the deficiency in CVID and autoimmunity had inferior suppressive function − antibodies.29 In addition, some patients with CVID were shown when cocultured with autologous CD4+CD25 T cells, to carry very dominant, stable CD8 clonotypes over time.29 although it is not clear if this phenomenon is primary or sec- Consistent with the notion of an underlying antigenic driver, a ondary, such as thymic sequestration by chronic infections.42 unique set of hyperexpanded TCRβ complementarity determin- CTLA-4 haploinsufficiency had been identified in cohorts of ing region 3 (CDR3) sequences could be found among patients patients with CVID and impaired Treg functions.48 49 An with CVID.
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