Whether or not a host organism mounts a protective immune response to invading pathogens is determined by a number of factors, including the genetic makeup of the host. Here, the role of a particular protein, H2-O, in the response against viruses and bacteria is explored in depth. The loss-of-function of H2-O in the I/LnJ strain of mice is identified as dependent on three amino acid mutations in the Ig domain of the H2-Oβ protein; however, the precise mechanism why polymorphism in this domain of the protein alters its function is not yet clear. We hypothesize it may be due to Ig-domain mediated interaction between H2-Oβ and novel factors yet to be identified. Supporting this hypothesis, we have discovered that two additional loci (other than H2-O, H2-M, or MHC-II) control antigen presentation and work to uncover the identities of the genes encoded in these loci is currently underway. Our current data suggest that loci on chromosomes 1 and 15 harbor these two factors. Classical MHC proteins influencing H2-O-dependent antibody responses was also investigated. While BALB/cJ mice harboring the MHC locus from the I/LnJ strain (H2J-congenic mice) mount potent neutralizing antibody responses against both MMTV and MuLV, H2-O deficiency alone only confers protection from MMTV and not MuLV. The lack of response against MuLV appears to be due to the H2d haplotype of MHC present in the BALB/cJ strain, as H2b-congenic BALB/cJ mice (BALB.B mice) are capable of producing neutralizing antibodies against the virus, although at lower titers than H2J-congenic BALB/cJ mice. While the response of H2-O-deficient mice on the C57BL/6J background mount neutralizing antibody responses against MMTV upon infection, the response of these animals to bacteria was completely unexplored. H2-O was found to influence multiple microbial communities, and our data suggest this may be independent of the quantity or specificity of IgA present in the gut. H2-O-deficient mice were also found to be more resistant to persistent colonization by the bacterium Staphylococcus aureus as well as restrict early phase replication of the bacterium Citrobacter rodentium. Study of the mechanism of H2-O control of these pathogens is underway, but preliminary experiments suggest a dependence on B cells in the S. aureus infection model. The resistance of H2-O-deficient animals to various pathogens in our studies made us question the physiological importance of this protein (as multiple models of infection suggested H2-O was maladaptive). The predominant hypothesis in the field of H2-O biology proposed H2-O played a role in the prevention of autoimmune disease, but conclusive studies to this end were lacking. To address this gap, we tested the susceptibility of H2-O-deficient mice in three models of autoimmunity, each utilizing a distinct genetic background. We did not find any evidence to suggest H2-O prevents autoimmunity. Instead, we found evidence to suggest H2-O is important in the restriction of a γherpesvirus, which exploits H2-O expressing cells during its replication. This suggests the physiological function of this gene may be related to high prevalence of such infections during the course of mammalian evolution. Determining the true importance of a gene during infection requires the use of physiologically relevant infection systems. H2-O deficiency is not sufficient to confer neutralizing antibody responses to C57BL/6J mice when infected via breastmilk, the natural route for MMTV. Mice infected as neonates by their mother’s viremic breastmilk exhibit life-long unresponsiveness to viral antigens. The role of H2-O in the induction or maintenance of this critical viral tolerance was explored. We found that H2-O-deficient neonatally infected mice were still partially tolerant to viral antigens, but to a lesser degree than H2-O-sufficient mice. However, H2-O-deficient mice did not exhibit any overall lack of oral tolerance to other dietary antigens, suggesting H2-O plays a role in the induction or maintenance of this virus-specific tolerance. It is tempting to speculate that MMTV may exploit H2-O in order to induce a state of immunological unresponsiveness against itself. In addition, we tested if H2-O-deficient splenocytes transferred into neonatally infected hosts would produce antibodies, or if this response would be suppressed in a tolerant host. We found that H2-O-deficient (but not H2-O sufficient) splenocytes transferred into tolerant hosts were able to produce antibodies, suggesting tolerance may be induced in a B-cell intrinsic fashion.