222 Infectious Disorders – Drug Targets, 2012, 12, 222-231 B Cells: Programmers of CD4 T Cell Responses Tom A. Barr*, Mohini Gray and David Gray Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3JT, UK Abstract: B cells are once again gaining prominence as important programmers of CD4 T cell responses. With wide- spread use of B cell depletion therapy in the clinic, proving effective in treating diseases previously considered T cell- mediated, the time is right for a re-appraisal of the B cell. Though typically considered weak, Th2 driving APC, it is now clear that they are necessary for a robust and long-lived CD4 T cell response in many settings. The sphere of B cell influ- ence extends well beyond that of simply antibody production; antigen presentation, cytokine secretion, costimulation and development of lymphoid tissue architecture are all critical aspects of B cell immunobiology, the absence of which has se- rious impacts for T cell priming and memory. The aim of this review is to look at non-antibody mediated B cell function and to ask how, where and when do B cells influence the CD4 T cell response? Keywords: B cell, T cell, antigen presentation, TLR, memory. INTRODUCTION programme the CD4 response. Although B cells are not “professional” with regard to the diversity of antigens they The term “professional” antigen presenting cell (APC) can present, they are exquisite APCs for their specific anti- was first coined by Lassila, Vainio and Matzinger in 1988, gen. Thus DCs, though “professional”, can be viewed as a following the demonstration that dendritic cells (DCs) and jack of all trades, whereas the “amateur” B cell is the master macrophages are necessary and sufficient for T cell priming of one!. [1] Whilst the fact remains that initiation of the immune re- sponse is dependent upon the “professional” APC, a role for Increasing use of B cell depletion therapies (BCDT) in B cells in T cell priming and maintenance, though for years the clinic has lead to a revival in interest in B cells and is controversial, now seems irrefutable. forcing a re-appraisal of their role in orchestrating immunity; responses previously considered predominantly T cell medi- The potential of B cells to influence the CD4 T cell re- ated are proving highly responsive to B cell depletion ther- sponse was first demonstrated in 1982 by Ron et al who apy in a way not reconcilable by ablation of auto-antibody showed a failure of proliferative T cell responses to protein [16, 17]. Thus, factors other than antibody secretion by B antigens in B cell depleted mice [2]. Since these early ex- cells are also at play here. Ablation of B cells at defined periments, a requirement for B cells in robust T cell immu- points in the immune response also removes the complica- nity has been demonstrated in many models; including sal- tion of developmental issues seen in B cell deficient mice, monella [3, 4], malaria [5-7], coronavirus [8] and herpesvi- and thus impacts on T cell responses can be more directly rus [9] infections. These studies have not been without con- attributable to the transient depletion. troversy. Given gross abnormalities seen in genetically- modified B cell deficient mice, including aberrant lymphoid The questions of what aspects of B cell biology influence organogenesis [10], reduced T cell numbers [11] and loss of T cell responses and where and when these interactions oc- follicular DC [12], directly attributing the T cell defects in cur remain unclear. The aim of this review is to reconsider these studies to a lack of B functionality per se has been the B cell, to look beyond their role as antibody producers problematic. In particular, a role for B cells in T cell priming and ask how do they programme the CD4 T cell response?. is highly contentious, with demonstrations that the potent antigen presenting capacity of antigen-specific B cells is INNATE AND ADAPTIVE SIGNALS IN B CELL AC- reserved for re-activation of memory cells [1, 13, 14]. TIVATION Relegation of B cells to the “amateur” league has left Professional APC become activated by sensing patho- them as under-appreciated participants in the T cell response. gens and/or danger signals in the environment, through their In particular, the potency of an antigen specific B cell to pre- expression of a range of receptors for pathogen-associated sent antigen to primed or memory T cells is considerable molecular patterns (PAMPS), (e.g. TLRs, NLRs and RLRs) [15]. Given that memory is the hallmark of adaptive immu- [18, 19]. These receptors allow the APC to sense local dan- nity, the holy grail of vaccine design, and when directed ger cues and provide an immunological context in which to against self-antigens, the cause of chronic autoimmunity, it is appropriately respond. This activation signal, often called important that we do not lose sight of the B cells’ capacity to ‘signal 0’, represents the primary activation pathway for in- nate APC, driving maturation following antigen acquisition and their subsequent migration from the periphery to T cell *Address corresponding to this author at the Institute of Immunology and Infection Research, University of Edinburgh, Ashworth Laboratories, zones of secondary lymphoid structures. B cells on the other King’s Buildings, West Mains Road, Edinburgh, EH9 3JT, Tel: +44 131 hand, through their dual expression of hypervariable B cell 650 5488; Fax: +44 131 650 7322; E-mail: [email protected] 2212-3989/12 $58.00+.00 © 2012 Bentham Science Publishers B Cells: Programmers of CD4 T Cell Responses Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 3 223 receptors (BCR) and germline encoded PAMP receptors, with appropriately armed T cells. For example, we have have two primary pathways for activation. TLR on B cells, shown that B cells stimulated with CpG rapidly shed as with professional APC, sense a broad range of pathogenic CD62L, which focuses them to the spleen during Salmonella patterns and cause direct activation, proliferation and matu- infection [33]. ration [20, 21]. The BCR however is highly specific, recog- One of the most important outcomes of TLR stimulation nising defined epitopes on antigens in their native conforma- of B cells is the induction of cytokine production [21]. In tion. This specificity lies at the heart of B cell clonal selec- particular IL-10 and IL-6 are produced in significant quanti- tion and expansion. Unlike innate APC, B cells must com- ties following TLR stimulation, pointing to potential regula- pete for the affections of T cells within the germinal centre, tory and pro-inflammatory roles for cytokine producing B with the fittest B cells profiting from T cell help and prolif- cells. Other cytokines are reported to be produced following erating as the immune response matures [22]. The influence TLR stimulation; for example IFN is secreted when B cells of B cells on T cell responses is generally attributed to these are stimulated with combinations of TLRs (eg. TLRs 2, 4 later stages of the response. However the sphere of influence and 9) [21]. Production of immunomodulatory cytokines is of B cells is now recognised to extend to the primary re- an area of great interest at the moment, and is dealt with in sponses through their expression of a diversity of innate re- more detail below. ceptors. ANTIGEN-SPECIFIC ACTIVATION OF B CELLS INNATE ACTIVATION OF B CELLS VIA TLRS - VIA BCR - SIGNAL 1 SIGNAL 0 The BCR is a unique receptor for cellular activation; it Both human and mouse B cells express many of the has dual functionality acting both as a mechanism to initiate TLRs. B cells respond rapidly and robustly to stimulation via signalling cascades and as a means to internalise antigen for these receptors (see [20, 23-25] for reviews). Of the TLRs processing and presentation. During B cell development the expressed by B cells, TLR4 and TLR9 (receptors for LPS BCR is pivotal to controlling B cell fate, with ligation to and CpG respectively) have been the most extensively stud- self-antigens leading to anergy or deletion. Once mature B ied. LPS has long been known to act as a B cell mitogen, cells enter the periphery, as transitional B cells, the BCR causing activation and polyclonal expansion of B cells irre- becomes the principal receptor for activation and prolifera- spective of BCR reactivity through complex binding to LPS- tion. Engagement of the BCR by antigen leads to phosphory- binding protein (LBP), CD14 and TLR4 [26]. B cells also lation of the intracellular ITAM tyrosines by LYN, SYK and express high levels of the TLR9 receptor. The outcomes of SH2 kinases resulting in the initiation of a variety of signal- TLR stimulation are diverse and there are several points at ling cascades, inducing activation and proliferation of the B which such innate activation of B cells can impact on the T cell (see [34] for review). cell response. Following BCR mediated activation B cells rapidly Perhaps the most obvious impact of TLR stimulation is upregulate the expression of numerous co-stimulatory mole- the influence on antibody secretion and this in turn influ- cules; key players in T:B interactions and the mediators of ences antigen opsonisation. Complexing of antigen with an- the cognate interactions known as T cell “help”. As with tibody has an adjuvant effect, enhancing uptake and the effi- innate activation, BCR ligation also influences the secretion ciency of processing and presentation by APC. The require- of cytokines. Though BCR ligation alone does not seem to ment for TLR ligation on B cells as a necessary prelude to a induce cytokines, this activation signal often strongly syner- class-switched T dependent antibody response has been con- gises with other signals such as TLR (e.g.