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The Essential Role of DOCK8 in Humoral Immunity Disease Markers 29 (2010) 141–150 141 DOI 10.3233/DMA-2010-0739 IOS Press The essential role of DOCK8 in humoral immunity Katrina L. Randalla,b, Teresa Lambec, Chris C. Goodnowa and Richard J. Cornallc,∗ aJohn Curtin School of Medical Research, The Australian National University, Canberra ACT, Australia bDepartment of Immunology, The Canberra Hospital, Garran, ACT, Australia cNuffield Department of Clinical Medicine, Oxford University, UK Abstract. The processes that normally generate and maintain adaptive immunity and immunological memory are poorly under- stood, and yet of fundamental importance when infectious diseases place such a major economic and social burden on the world’s health and agriculture systems. Defects in these mechanisms also underlie the many forms of human primary immunodeficiency. Identifying these mechanisms in a systematic way is therefore important if we are to develop better strategies for treating and preventing infection, inherited disease, transplant rejection and autoimmunity. In this review we describe a genome-wide screen in mice for the genes important for generating these adaptive responses, and describe two independent DOCK8 mutant mice strains identified by this screen. DOCK 8 was found to play an essential role in humoral immune responses and to be important in the proper formation of the B cell immunological synapse. Keywords: DOCK8, germinal center, immunodeficiency, DOCK family, guanine exchange factor 1. Introduction cy, while also discovering the role of many genes im- portant in innate and adaptive immune responses [12]. The adaptive immune system of higher vertebrates is Identifying mouse models of individual immune defi- characterized by the ability to remember previous en- ciencies can also be important to inform us about hu- counterswith antigenand to respondmorequicklywith man disease, and provide insights into normal immune higher affinity antibodies, the second time an antigen is function. Characterization of the SAP−/− mice has encountered. In part, this is dueto long-livedbonemar- allowed new insights into the extent of cellular abnor- row resident plasma cells and memory B cells which malities in X-linked lymphoproliferative disease [35, are formedduringthe primary response in a specialized 45], while investigations of WASp −/− mice has pro- structure within the secondary lymphoid tissue known vided insights into B cell abnormalities in patients with as the germinal center [3]. The exact mechanisms re- Wiskott-Aldrich syndrome [39]. Using mouse models sponsible for the development and persistence of these to look at the cellular consequences of mutation can adaptive responses are not known, and a systematic ap- be useful in situations in primary immunodeficiency in proach to gene discovery may allow new insights into which it is difficult to differentiate the cellular conse- these processes. quences of the mutation from the consequences of in- Genome wide screening in patients with particular fection arising due to the mutation, or from the effects primary immunodeficiencies has identified the genetic of antibiotic or antiviral medications used to treat the cause in many monogenic forms of immunodeficien- infections. Mouse models also provide a genetically homogenous environment to study the cellular conse- quences of the mutation and differentiate these from ∗Corresponding author: Richard J. Cornall, Nuffield Department of Clinical Medicine, Oxford University, UK. Tel.: +44 1865 287790; consequences that may arise due to genetic polymor- Fax: +44 1865 287787; E-mail: [email protected]. phisms within a population. ISSN 0278-0240/10/$27.50 2010 – IOS Press and the authors. All rights reserved 142 K.L. Randall et al. / The essential role of DOCK8 in humoral immunity In this review we discuss the recent identification of ciencies in germinal center formation and affinity mat- murineDOCK8mutationsthroughtheuseofagenome- uration in response to T dependent antigens [60]. wide screen for mice with abnormal vaccination re- The mice were first immunized with chicken gam- sponses, and the consequences for humoral immunity maglobulin (CGG) coupled to arsonate hapten (ABA) of DOCK8 mutations. We also discuss the DOCK fam- and heat-killed Bordetella pertussis bacilli. The pro- ily of proteins in mice, and highlight particular DOCK tein CGG normally elicits an IgG1 response, while the proteins thought to play a role in the immune system B. pertussis elicits an IgG2c response and these anti- and as well as discussing the parallels with the function bodies are detected in plasma 14 days after the initial that DOCK proteins are thought to play in the nervous immunization using an enzyme linked immunoassay system. (ELISA). Mice that produce a robust antibody reaction to CGG but do not respond to B. pertussis are inferred to have a low Th1 response, while those with normal 2. The use of ENU mutagenesis to identify novel responses to B. pertussis and low response to CGG are causes of immunodeficiency inferredtohavealowTh2response. Thoseinwhomthe response to both antigens is compromised, are classed as having deficiency of T-dependentimmune responses Long-lived plasma cells and memory B cells pro- (or mis-injection). To screen for mice with defects in duced during adaptive immune responses form the ba- secondaryor memoryresponses, themicewereboosted sis of vaccination and protection from disease [3,59], with ABA-CGG 6 weeks after the first immunization, yet the genes, mechanisms and processes behind the and antibodies detected by ELISA in plasma collected production of these important cell types are not fully six days later. In C57BL/6 mice, antibodies to the ar- understood. The genes important in the production of sonate hapten only emerge after mutation in germinal the adaptive immune responses are also likely to be de- centers changes the specificity of the antibodyso that it fective in those human primary immunodeficiencies in no longer cross-reacts with DNA [23], and antibodies which a genetic cause has not yet been found (such as to this particular compound also indicate the presence in the majority of cases of common variable immunod- of germinal centers in the immune response. At the eficiency (CVID)). time of the booster injection, the mice were also immu- One way to search for these novel genes and mech- nized with NP-Ficoll to test the T-independentrespons- anisms is to study animals with heritable defects in the es, with anti-NP antibodies also detected by ELISA six immune response that are generated with the chemical days later [60]. mutagen ethylnitrosurea (ENU). Male C57BL/6 mice injected with ENU develop single nucleotide substitu- ∼ tions at a frequencyof 1 per million base pairs in their 3. The discovery of DOCK8 immunodeficient mice spermatogonial stem cells [52,60], which are transmit- ted to progeny, thus creating libraries of mutant mice Two novel mutant mouse strains were identified due that can be screened for heritable phenotypes. Of those to abnormalities in the vaccination screen described that lead to a detectable phenotypic effect, two thirds above– captain morgan(cpm)andprimurus(pri). Both interfere with the function of a protein due to an amino were found to have recessive mutations in a poorly acid substitution, while one-third lead to aberrant splic- characterized 190 kDa guanine nucleotide exchange ing [28]. We have already shown how the characteri- factor (GEF) called DOCK8. zation of strains from screens for autoimmune disease The cpm mutation was in the exon 20 splice donor and lymphocyte development – such as sanroque, tiny sequence and yielded frame shift mutations that elimi- and most recently themis [27,46,61] – can reveal new nated the catalytic GEF domain due to truncating mu- and unexpected information relevant to human disease. tations. The GEF domain is also known as DOCK We have now used the same strategy to screen for homology region 2 (DHR2) and is one of two con- ENU mutant strains with immunodeficiency detected served regions within all DOCK proteins (the other be- by an abnormal antibody response to immunization. ing DHR1). In pri, an exon 43 mutation caused substi- The immunization screen was devised to screen for tution of a conserved Ser 1827 to Pro, which would be mutations affecting the polarization of the immune re- expected to break the predicted alpha helical structure sponse to either TH1 or TH2, to look for deficient re- of the same GEF domain. In DOCK9, where the GEF sponses to T – independent antigens, and lastly defi- domain structure has recently been solved in complex K.L. Randall et al. / The essential role of DOCK8 in humoral immunity 143 Fig. 1. Two independent mutations in mouse DOCK8. Schematic representation of the structure of murine DOCK8 showing the position of the two conserved protein domains – DHR1 and DHR2. The position of two independent mutations (cpm and pri) that arose through ENU mutagenesis are shown. Underlined text represents the sequence of Exon 20, while bold type indicates the mutated nucleotide. Figure modified from Fig. 3a original published in Nature Immunology; 10: 1283–1291 [53]. with Cdc42 [66], the serine is conservedand lies within ment there was a two-fold reduction in na¨ıve CD8 and alpha helix 6 that forms multiple contacts with Cdc42. CD4 T cells in the blood, spleen and Peyer’s patches The position of the two mutations and the conserved of both strains, and preservation of cells with an ac- DHR1 and DHR2 domains within the DOCK8 protein tivated/memory CD44hi phenotype [[53], unpublished are shown in Fig. 1. data.] The vaccination responsesin both cpm and pri mouse Chemotaxis assays carried out using the three main strains were further characterized with the antigens chemotactic factors for germinal center, MZ, and B1 used in the initial vaccination screen. Both strains failed cells – S1P,CXCL12 and CXCL13 – foundthat mutant to developa sustained IgG response after a primary im- and wild-type spleen B cells had similar chemotactic munization with CGG despite having a normal initial responses. Likewise, in vivo accumulation of B cells in lymph nodeswasindistinguishable between mutant and immune response and normal polarization to TH1 and wildtype (WT) B cells in competitive mixed chimeras.
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