؉ T-cell counts (4 to 8 times longer), while responses to variable epitopes presented by B35 alleles (DL9 and IL9) resulted in more rapid progression. The plasma viral load was higher in B57/58 ؉ and B27 ؉ subjects lacking the conserved B57/58-and B27-restricted responses. The presence of certain B57/58-, B27-, and B35-restricted HIV-specific CD8 ؉ T-cell responses after primary HIV-1 infection better defined disease progression than the HLA genotype alone, suggesting that it is the HIV-specific CD8 ؉ T cells and not the presence of a particular HLA allele that determine disease progression. Further, the most effective host CD8 ؉ T-cell responses to HIV-1 were prevalent within an HLA allele, represented a high total allele fraction of the host CD8 ؉ T-cell response, and targeted conserved regions of HIV-1. These data suggest that vaccine immunogens should contain only conserved regions of HIV-1.

It is well established that the route of infection affectsRespiratory enteric orphan virus (reovirus) has been used as a model viral pathogen to study virus-host interactions at mucosal surfaces and in the periphery. Reovirus is a nonenveloped, segmented double-stranded RNA virus (31) that replicates and elicits both humoral and cell-mediated immunity following oral or parenteral infection (7,13,14,16,25). After gaining access to the intestinal tissue via the M cells of the Peyer's patches (PP) (46), reovirus serotype 1 strain Lang (T1/L) infection of immunocompetent mice causes a self-limited disease of enterocytes of the crypts of Lieberkuhn adjacent to the PP of the distal ileum (37). In response, virus-specific cytotoxic T lymphocytes (CTLs) are induced within the PP (25). CTLs migrate via efferent lymphatic vessels to the mesenteric lymph nodes and then through the thoracic duct lymph and the systemic circulation to the spleen (25) or to intestinal mucosal sites, such as the intestinal intraepithelial lymphocyte (IEL) compartment (8, 9, 24). Parenteral infection with reovirus induces virus-specific CTLs in the draining peripheral lymph nodes and spleen (22,45).Although the humoral immune response to reovirus is influenced by microenvironmental or cellular factors at the anatomic site of infection (7,26,44), it is not known whether intestinal reovirus infection results in a CTL response distinct from that following parenteral infection. Most reovirus-specific CTLs are CD8␣␤ϩ TCR␣␤ ϩ Thy-1 ϩ and major histocompatibility complex (MHC) class I restricted (25). In addition, reovirus-specific CD8 ϩ CTLs induced in the PP following enteric infection and in the lung following respiratory infection express the unusual cell surface marker called germinal center and T antigen (23,44). Intratracheal instillation of reovirus elicits an unusual population of cytotoxic CD4 ϩ CD8␣␤ ϩ TCR␣␤ ϩ T cells (34), suggesting that unique CTL populations might be induced by infection at distinct anatomic locations. Furthermore, enteric reovirus T1/L infection of C3H mice has been shown to elicit CD8␣␤ ϩ CTL populations expressing V␤12 and V␤17, with minor populations expressing V␤2, V␤7, V␤9, and V␤14 among the IELs (8). These CTL populations were thought to be representative of the CTL response primed in the PP following oral infection with reovirus T1/L (9), although some might have been derived in situ, given the uncertain ontogeny of the IEL.There are several reasons why CTLs induced following oral infection could be different from those induced parenterally. During enteric reovirus infection, the ingested virions undergo pancreatic chymotryptic proteolysis of the outer coat proteins in the duodenum to yield infectious intermediate subviral particles (3). This processing within the lumen of the small intestine could potentially generate antigenic determinants distinct from those generated in the systemic periphery. Additionally, cleaved viral antigens might be taken up by intestinal absorptive epithelial cells (32,42), which expr...

Previous studies from this laboratory have shown that the injection of mice with an affinity-purified goat antibody to mouse IgD (GaM delta) induces T-independent polyclonal increases in: 1) B cell DNA synthesis, and 2) expression of surface Ia antigen and receptors for T helper factors, 1 to 2 days after injection. In addition, T-independent polyclonal increases in B cell number and IgG1 secretion are observed 6 to 7 days after injection. The administration of normal goat IgG (GIgG) along with GaM delta has been shown to augment GaM delta-induced polyclonal IgG1 secretion. To obtain information about the characteristics of the T help that is required for polyclonal antibody production in this model system, we investigated: 1) the length of the period during which GaM delta must be present to induce day 7 polyclonal antibody production, and 2) the kinetics of the induction of splenic T cell DNA synthesis. We found that GaM delta can be neutralized 3 days after injection by the administration of IgD without decreasing day 7 polyclonal IgG1 secretion, as long as mice are given GIgG at the time that GaM delta is neutralized. In contrast, polyclonal IgG1 secretion is greatly inhibited if GaM delta is neutralized 1 to 2 days after injection or if GaM delta is neutralized 3 days after injection, but GIgG is not administered at this time. Because GIgG can stimulate activated GIgG-specific T cells to secrete helper factors, but, unlike GaM delta cannot focus GIgG-specific T help polyclonally onto B cells, these findings suggest that nonspecific T help, rather than antigen-specific T help, is required in this system after day 3 for the induction of polyclonal IgG1 secretion. Determination of the kinetics of the induction of T cell DNA synthesis in this system by in vivo [3H] thymidine incorporation studies, as well as dual laser fluorescence-activated cell sorter analysis of T and B cell DNA content, indicate that T cells are induced to synthesize DNA 2 days after GaM delta injection and reach plateau rates of DNA synthesis 3 days after injection. Taken together, the GaM delta neutralization experiments and DNA synthesis studies suggest that one reason that GaM delta is required for 3 days in this system is to allow maximal activation of GIgG-specific T cells, which when stimulated later by GIgG secrete nonantigen-specific helper factors that induce GaM delta-activated B cells to secrete IgG1.

We describe the development of T cell lines possessing a binding specificity for syngeneic T15 idiotopes (Id) expressed on phosphorylcholine (PC)-reactive Ig. The lines were obtained by cultivation of BALB/c splenic T cells with T15 Id+ stimulator cells BCg3R-1d, a BALB/c lymphoma transfected with genomic sequences mu and kappa with S107 (T15) variable regions. Resulting Thyl-2+, L3T4+ cell lines depend on the T15 Id+ BCg3R-1d cells for growth and demonstrate the ability to bind TEPC15, a S107 germline-encoded, PC-specific Ig alpha. The specificity of the 125I-TEPC15 binding was studied in a competitive RIA with various unlabeled Ig. The isolated H and L chains of TEPC15 failed to inhibit the 125I-TEPC15 binding, and the T15-, PC-binding proteins M603 (alpha) and M511 (alpha) inhibited the binding either poorly or not at all. Moreover, the T cell lines had a discriminatory binding specificity for various T15+ Ig that are somatic variants of TEPC15 and that differ from each other in discrete, conformational Id (epitopes) detectable with specific monoclonal anti-Id. The T cell lines could be grouped according to their binding patterns, which were comparable to the recognition patterns of certain monoclonal anti-Id. These data suggest the existence of T cells with specificity for serologically-defined determinants of syngeneic idiotypes.