Protective immunity to chronic and acute viral infection relies on both the innate and adaptive immune response. Although neutralizing antibody production by B cells and cytotoxic activity of CD8+ T cells are well-accepted components of the adaptive immune response to viruses, identification of the specific role of CD4+ T cells in protection has been more challenging to establish. Delineating the contribution of CD4+ T cells has been complicated by their functional heterogeneity, breadth in antigen specificity, transient appearance in circulation, and sequestration in tissue sites of infection. In this minireview, we discuss recent progress in identifying the multiple roles of CD4+ T cells in orchestrating and mediating the immune responses against viral pathogens. We highlight several recent reports, including one published in this issue, that have employed comprehensive and sophisticated approaches to provide new evidence for CD4+ T cells as direct effectors in antiviral immunity.

Recently several cell lines have been identified with mutations in a major histocompatibility complex (MHC)-linked protein that lead to defects in class II-restricted antigen presentation and a defect in the formation of class II SDS-stable dimers. The defect in these cells has recently been shown to result from the inability to express the MHC-encoded nonclassical class II molecule called DM. To further examine the role of DM in class II-restricted antigen presentation, we asked if this defect would equally affect different allelic and species variants of class II molecules. To investigate this, we transfected the parent cell lines T1 and 8.1.6 and their respective antigen presentation mutants T2 and 9.5.3 with the genes encoding I-Ad and examined the derived transfectants for their ability to present antigen, the conformation of I-Ad at the cell surface, association of I-Ad with invariant chain (Ii), and the ability to form I-Ad SDS-stable dimers. The lack of functional DM expression did not affect any of the anti-I-Ad monoclonal antibody (mAb) epitopes tested or the ability of I-Ad to associate and dissociate with Ii. Surprisingly, these studies also revealed that the antigen presentation defect observed for DR in the 9.5.3 cells did not compromise I-Ad-restricted antigen presentation. In addition, we found that the level of SDS-stable dimer formation did not correlate with antigen presentation capacity for I-Ad and that the amount of SDS-stable I-Ad dimer depends on the cellular context in which the class II molecule is expressed. Our results suggest that the ability to form SDS-stable dimer is not strictly correlated with class II-restricted antigen presentation. Finally, when two allelic forms of murine class II molecules were compared in the defective T2 cell line, it was found that I-Ak but not I-Ad forms SDS-stable dimers equivalent to that seen in the parental cell lines. Overall, our results suggest that DM may modulate rather than play a requisite role in I-Ad-restricted antigen presentation and SDS-stable dimer formation and that dependency on DM may be allele or species specific.

The murine Ia-associated chondrointin sulfate proteoglycan (CSPG) was studied both biochemically and immunochemically to determine the nature of its core protein. Chondroitinase ABC or chondroitinase AC treatment of the CSPG digested the chondroitin sulfate glycosaminoglycan, yielding a core protein that migrated with an apparent molecular weight of 38,000. Comparative V8 protease digestion of the CSPG core protein and conventional invariant glycoproteins yielded homologous peptides, indicating that the core protein and invariant chain were structurally similar. The purified CSPG and its core protein were both shown to react directly with the monoclonal anti-invariant chain antibody, In-1. Comparative tryptic peptide analysis by high performance liquid chromatography demonstrated coelution of the majority of the peptides from the invariant chain and the CSPG core protein. Collectively, these results indicate that the CSPG is an alternatively processed form of invariant chain.