T cell recognition of antigen-presenting cells depends on their expression of a spectrum of peptides bound to major histocompatibility complex class I (MHC-I) and class II (MHC-II) molecules. Conversion of antigens from pathogens or transformed cells into MHC-I- and MHC-II-bound peptides is critical for mounting protective T cell responses, and similar processing of self proteins is necessary to establish and maintain tolerance. Cells use a variety of mechanisms to acquire protein antigens, from translation in the cytosol to variations on the theme of endocytosis, and to degrade them once acquired. In this review, we highlight the aspects of MHC-I and MHC-II biosynthesis and assembly that have evolved to intersect these pathways and sample the peptides that are produced.

Pathways of Antigen Processing

Marginal Zone and B1 B Cells Unite in the Early Response against T-Independent Blood-Borne Particulate Antigens

BAFF, a member of the TNF family, is a fundamental survival factor for transitional and mature B cells. BAFF overexpression leads to an expanded B cell compartment and autoimmunity in mice, and elevated amounts of BAFF can be found in the serum of autoimmune patients. APRIL is a related factor that shares receptors with BAFF yet appears to play a different biological role. The BAFF system provides not only potential insight into the development of autoreactive B cells but a relatively simple paradigm to begin considering the balancing act between survival, growth, and death that affects all cells.

BAFF AND APRIL: a tutorial on B cell survival.

Only mature B lymphocytes can enter the lymphoid follicles of spleen and lymph nodes and thus efficiently participate in the immune response. Mature, long-lived B lymphocytes derive from short-lived precursors generated in the bone marrow. We show that selection into the mature pool is an active process and takes place in the spleen. Two populations of splenic B cells were identified as precursors for mature B cells. Transitional B cells of type 1 (T1) are recent immigrants from the bone marrow. They develop into the transitional B cells of type 2 (T2), which are cycling and found exclusively in the primary follicles of the spleen. Mature B cells can be generated from T1 or T2 B cells.

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B Cell Development in the Spleen Takes Place in Discrete Steps and Is Determined by the Quality of B Cell Receptor–Derived Signals

Recent advances in genomics and proteomics, combined with the facilitated generation and analysis of transgenic and gene-knockout animals, have revealed new complexities in classical biological systems, including the B-cell compartment. Studies on an 'old', but poorly characterized, B-cell subset--the naive, marginal-zone (MZ) B-cell subset--over the past two years have spawned an avalanche of data that encompass the generation and function of these cells. Now that the initial 'infatuation' is over, it is time to reconsider these data and generate some conclusions that can be incorporated into a working model of the B-cell system.

Marginal-zone B cells.

Antibody reactivity to self-antigens is a normal component of the immune system. To study the mechanism by which self-reactive B cells are generated and maintained, we analyzed B cell development in transgenic mice that express a rearranged VH81X heavy chain from the pre-immune repertoire. In these mice, > 95% of B cells express the transgene in association with a variety of kappa light chains but V kappa 1 C being the dominant light chain. These transgenic B cells with identical V kappa 1C-J kappa 5 joins do not normally secrete IgM in vivo, but antibodies derived from these B cells, through LPS activation in vitro or after hybridoma immortalization, are self-reactive and recognize an ubiquitous epitope(s) on intracytoplasmic proteins from different tissues. They have the phenotype and localization pattern of long-lived marginal zone B cells and their development in vivo is blocked by injection of soluble VH81X-V kappa 1CJ kappa 5 IgM antibody. The observations in this transgenic mouse provide evidence for positive selection of a population of self-reactive B cells. These B cells enter the peripheral pool of B cells where they localize in the marginal zone of the spleen and, in contrast to other transgene-expressing B cells, do not secrete IgM antibody.

Evidence for selection of a population of multi-reactive B cells into the splenic marginal zone.

Epistasis between MicroRNAs 155 and 146a during T Cell-Mediated Antitumor Immunity

B lymphocytes are regarded as professional antigen-presenting cells (APCs) despite their primary role in humoral immunity. Over the last two decades, studies designed to define the role of the B cells as APCs have generated discrepant results, showing that B cells are either unnecessary or required for T cell priming and either immunogenic or tolerogenic to T cells. The reasons for these discrepancies are not clear. Here we review mechanisms regulating B cell antigen presentation and the data derived from the major studies conducted by different groups representing each school of thought. In general it is clear that B cells process and present specific and nonspecific antigens differently. The presentation of specific antigen through the B cell antigen receptor occurs with very high efficiency and is associated with B cell activation, resulting in the activation of cognate T cells. In contrast, the presentation of nonspecific antigen by B cells is minimized and dissociated from B cell activation. As a result, B cells inactivate T cells that recognize nonspecific antigenic epitopes presented by B cells, or they induce regulatory T cell differentiation or expansion. These mechanisms serve to ensure effective production of high-affinity antigen-specific antibodies but minimize the production of nonspecific antibodies and autoantibodies.

The role of B lymphocytes as antigen-presenting cells.

Despite the unequivocal role of B lymphocytes as effecter cells in humoral immunity, studies have reported that B cells are tolerogenic. The impact of B cell-mediated tolerance and its underlying mechanisms are incompletely understood. Using primary B cells as APCs and allogeneic CD4 T cells as responder cells in mixed leukocyte reactions, we find that B cells preferentially expand FoxP3+ over FoxP3− CD4 T cells in the absence of exogenous cytokines. The preferential expansion of Foxp3+ T cells is further enhanced by a partial blockade of class II MHC-TCR interaction but diminished by stimulatory anti-CD28 Ab or at high B to T cell ratios. Gamma irradiation of B cells selectively abrogates their ability to expand isolated CD25+ but not CD25− CD4 T cells; exogenous IL-2 supplement can partially restore this function. B cell-expanded CD25+ T cells express high levels of FoxP3 and are highly inhibitory in an Ag-specific manner.

Cutting edge: primary B lymphocytes preferentially expand allogeneic FoxP3+ CD4 T cells.

Human histocompatibility leukocyte antigen (HLA)-DO, a lysosomal resident major histocompatibility complex class II molecule expressed in B cells, has previously been shown to be a negative regulator of HLA-DM peptide loading function. We analyze the expression of DO in human peripheral blood, lymph node, tonsil, and bone marrow to determine if DO expression is modulated in the physiological setting. B cells, but not monocytes or monocyte-derived dendritic cells, are observed to express this protein. Preclearing experiments demonstrate that ∼50% of HLA-DM is bound to DO in peripheral blood B cells. HLA-DM and HLA-DR expression is demonstrated early in B cell development, beginning at the pro-B stage in adult human bone marrow. In contrast, DO expression is initiated only after B cell development is complete. In all situations, there is a striking correlation between intracellular DO expression and cell surface class II–associated invariant chain peptide expression, which suggests that DO substantially inhibits DM function in primary human B cells. We report that the expression of DO is markedly downmodulated in human germinal center B cells. Modulation of DO expression may provide a mechanism to regulate peptide loading activity and antigen presentation by B cells during the development of humoral immune responses.

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Regulated expression of human histocompatibility leukocyte antigen (HLA)-DO during antigen-dependent and antigen-independent phases of B cell development.

Xinjian Chen

Papers

Evidence for selection of a population of multi-reactive B cells into the splenic marginal zone.

Epistasis between MicroRNAs 155 and 146a during T Cell-Mediated Antitumor Immunity

The role of B lymphocytes as antigen-presenting cells.

Cutting edge: primary B lymphocytes preferentially expand allogeneic FoxP3+ CD4 T cells.

Regulated expression of human histocompatibility leukocyte antigen (HLA)-DO during antigen-dependent and antigen-independent phases of B cell development.