Acquisition of functional MHC class II/peptide complexes by T cells during thymic development and CNS-directed pathogenesis☆
Introduction
Mouse [1], [2], [3], [4], rat [5], [6], [7], [8], and human [9], [10], [11], [12] T cells express MHCII1 during immune responses and mediate MHCII-restricted antigen presentation. Compared to other types of APC, T cell-mediated antigen presentation is less stimulatory and typically results in anergy or apoptosis of responding T cells [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]. For this reason, T cell-mediated antigen presentation may serve as an important regulatory mechanism. Previous studies have shown that recognition of peptides as partial agonists promotes prolonged expression of MHCII/peptide complexes and persistent antigen presentation [23], [24], [25]. Because the T cell repertoire is selected by recognition of partially agonistic self-peptides [26], [27], [28], [29], the positively selected T cell repertoire may mediate chronic low-intensity presentation of self-antigen as a mechanism of peripheral tolerance [30], [31]. Recognition, acquisition, and presentation of MHCII/peptide complexes by positively-selected T cells may result in T cell-mediated antigen presentation to potentially pathogenic T cells in the periphery that by definition would be highly reactive to self. Homeostatic T cell-mediated presentation of self may thereby purge T cells capable of mediating autoimmune disease and may thereby constitute an important mechanism of peripheral tolerance.
MHCII may be directly synthesized by T cells or may be synthesized by professional APC and acquired as pre-formed MHCII/peptide complexes by T cells [32], [33], [34], [35], [36]. T cells may acquire membrane-bound MHCII by absorption either directly from the APC cell surface or possibly from packaged vesicles (exosomes) [37]. The ability of T cells to adsorb MHCII requires some degree of T cell activation and is a typical consequence of antigen recognition. Previous studies have shown that partial activation of T cells, which would be the case for positive thymic selection, is sufficient to drive T cell acquisition of MHCII [25]. Accordingly, studies of radiation bone marrow chimeras revealed that murine thymic T cells acquire MHCII in vivo [38]. That is, in radiation bone marrow chimeras, donor thymocytes acquired allogeneic host I-A molecules from radioresistant thymic APC of the recipient whereas synthesis of MHCII by thymic T cells was not detected in vitro.
This study provides evidence that thymic rat T cells acquire functional MHCII/peptide complexes from radioresistant thymic APC by a mechanism associated with the induction of antigen-specific tolerance. Furthermore, encephalitogenic mouse T cells acquire MHCII from professional APC in the CNS during paralytic EAE.
Section snippets
Animals and reagents
Lewis rats (Harlan-Sprague Dawley, Indianapolis, IN), C57BL/6 mice, Balb/c mice, and B10.PL mice (Jackson) were maintained at East Carolina University School of Medicine. MBP Ac1-11-specific T cell receptor transgenic mice were generously provided by Dr. Juan Lafaille [39]. MBP was purified from rat or guinea pig spinal cords (Rockland). The anti-I-A Y3P IgG2a, anti-mouse I-Ad MKD6 IgG2a, anti-mouse CD4 GK1.5 IgG2b, anti-mouse CD8 53–6.72 IgG2a, anti-mouse I-Ab AF6-120.1 IgG2a, anti-mouse I-As
MHCII expression on thymic and splenic T cells in normal mice and rats
Even though normal T cells are considered to lack MHCII in vivo, we invariably detected significant levels of MHCII I-A molecules on both rat and mouse T cells from both spleen and thymus. As shown in Fig. 1, I-A molecules were detected on C57BL/6 TCR+ T cells stained with the Y3P mAb in both thymic and splenic T cell fractions. Fluorescence of C57BL/6 T cells stained with the isotype control MK-D6 anti-I-Ad mAb was no different compared to control groups lacking primary mAb (data not shown).
Discussion
This study provides evidence that significant levels of cell surface I-A exist on normal T cells in thymus and spleen in both rats and mice. Expression of T cell surface I-A was haplotype-specific and was detected at essentially equal levels on splenic CD4+ and CD8+ single-positive T cells. Overall, levels of I-A on T cells were 10–50-fold lower than corresponding levels on splenic professional APC. T cell surface I-A was implicated in antigen presentation because nonadherent radiosensitive
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This study was supported by a research grant from the National Multiple Sclerosis Society.