Two new papers converge in concluding that B cells can play an important role in sustaining CD4 T cell memory, via a mechanism that is independent of antibody production. One study involves genetically manipulated mice, the other looks at people with genetic disorders that impact B cell numbers and function. The data appear consistent with reports of an increased incidence of viral, bacterial, and fungal infections in individuals that have received B cell-depleting therapies. The human study also identifies possible differences between pathogens, as influenza-specific T cell memory did not appear to be impacted in the same way as responses to meningococcus.
As Jason Whitmire and colleagues point out in their paper, these findings have implications for interpreting studies that use experimental B cell depletion as a means to evaluate the role of neutralizing antibodies in protecting against disease. Several such studies have been conducted in the SIV model, for example this report in J Virology from 2007. The authors of the paper write: “Our results suggest that antibodies are critical for protecting SIV-specific memory CD4 T helper cells from devastating destruction in the initial stages of infection. Thus, monkeys that produce anti-SIV antibodies by week 4 PI are able to live for extended periods because SIV-specific CD4 T helper cells can persist and maintain effective antiviral CD8 T-cell responses.” However, Whitmire et al found that the absence of B cells caused CD4 T cell responses to disappear with very similar kinetics (at the end of the primary response, when a memory CD4 T cell response would normally be expected to develop and persist). These new data may therefore offer an alternate explanation of the loss of CD4 T cell memory in the SIV study.
Coincidentally, at the upcoming Conference on Retroviruses and Opportunistic Infections (CROI), which starts tomorrow in Montreal, there is a poster presentation regarding the impact of the B cell-depleting drug rituximab in people with HIV infection (poster #331, see below for the full reference and link to the CROI pocket program).
The Journal of Immunology, 2009, 182: 1868-1876.
doi:10.4049/jimmunol.0802501
Requirement of B Cells for Generating CD4+ T Cell Memory
Jason K. Whitmire2,*, Mary S. Asano, Susan M. Kaech, Surojit Sarkar, Lynn G. Hannum, Mark J. Shlomchik and Rafi Ahmed
* Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Emory Vaccine Center and Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA 30322; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and Department of Immunobiology and Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510
B cells can influence T cell responses by directly presenting Ag or by secreting Ab that binds to Ag to form immunogenic complexes. Conflicting evidence suggests that persisting Ag-Ab complexes propagate long-term T cell memory; yet, other data indicate that memory cells can survive without specific Ag or MHC. In this study, the roles of B cells and Ag-Ab complexes in T cell responses to lymphocytic choriomeningitis virus (LCMV) infection were investigated using B cell-deficient or B cell-competent mice. Despite normal lymphocyte expansion after acute infection, B cell-deficient mice rapidly lost CD4+ T cell memory, but not CD8+ T cell memory, during the contraction phase. To determine whether Ag-Ab complexes sustain CD4+ T cell memory, T cell responses were followed in B cell-transgenic (mIg-Tg) mice that have B cells but neither LCMV-specific Ab nor LCMV-immune complex deposition. In contrast to B cell-deficient mice, mIg-Tg mice retained functional Th cell memory, indicating that B cells selectively preserve CD4+ T cell memory independently of immune complex formation. An in vivo consequence of losing CD4+ T cell memory was that B cell-deficient mice were unable to resolve chronic virus infection. These data implicate a B cell function other than Ab production that induces long-term protective immunity.
Blood First Edition Paper, prepublished online February 6, 2009; DOI 10.1182/blood-2008-08-171587.
Begonia Morales-Aza, Sarah J Glennie*, Tomaz Pereira Garcez, Victoria Davenport, Sarah L Johnston, Neil A Williams, and Robert S Heyderman
Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol, United Kingdom
Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi
Department of Immunology, North Bristol NHS Trust, Bristol, United Kingdom
Faculty of Applied Sciences, University of West of England, Bristol, United Kingdom
The importance of T cells in the generation of antigen specific B cell immunity has been extensively described, but the role B cells play in shaping T cell memory is uncertain. In healthy individuals, exposure to Neisseria meningitidis in the upper respiratory tract is associated with the generation of memory T cells in the mucosal and systemic compartments. However, we demonstrate that in B cell deficient subjects with X-linked agammaglobulinemia (XLA), naturally-acquired T cell memory responses to meningococcal antigens are reduced compared with healthy controls. This difference is not seen in T cell memory to an obligate respiratory pathogen, influenza virus. Accordingly, we show that meningococcal antigens upregulate MHC class II, CD40, CD86/80 expression on mucosal and systemic associated B cells and that antigen presentation stimulates T cell proliferation. A similar reduction in N. meningitidis but not influenza antigen-specific T cell memory was seen in subjects with X-linked hyper IgM syndrome (X-HIM), implicating the interaction of CD40-CD40L in this process. Together, these data implicate B cells in the induction and maintenance of T cell memory to mucosal colonizing bacteria such as N. meningitidis, and highlight the importance of B cells beyond antibody production but as a target for immune reconstitution.
16th Conference on Retrovirses & Opportunistic Infections, Montreal, Canada, February 8-11, Abstract #331
A Critical Role for B Cells in Control of HIV Revealed by Rituximab Therapy
Kuan-Hsiang Huang1, G Cooke2, E Thomson2, S Fidler2, J Main2, D Muir2, J Weber2, A Frater1, M McClure2, and P Klenerman1
1 Univ of Oxford, UK and 2Imperial Coll London, UK
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