Tuberculosis (TB), a multi-organ infectious disease caused by virulent mycobacteria, most predominantly M. tuberculosis, remains one of the deadliest infectious diseases in human history. Bacillus Calmette-Guérin (BCG) vaccine, first implemented medically in 1921, has remained the only available vaccine for TB, although its protective effect is moderate. TB occurs in 5-10% of individuals exposed to those pathogens, while 90-95% remain asymptomatic (i.e.,latent infection or spontaneous clearance). This surprisingly large inter-individual variability has long attracted the attention of human geneticists. Classical twin-based genetic studies have demonstrated the presence of a substantial genetic risk of developing TB disease between monozygotic twins. Later, the clinical and genetic characterization of a rare and severe disease caused by weakly virulent and normally harmless mycobacteria, such as the BCG vaccine substrain, now recognized as Mendelian Susceptibility to Mycobacterial Disease (MSMD), demonstrated that IFN-γ is indispensable for antimycobacterial immunity in humans.Moreover, homozygosity for a common missense mutation P1104A in a protein TYK2 was discovered as the first genetic predisposing factor to TB in humans. TYK2 P1104A selectively impairs IL-23-dependent IFN-γ production by lymphocytes.In light of these findings, I hypothesized that a partial impairment of IFN-γ immunity due to known or novel genetic defects underlies vulnerability to TB in humans. I characterized three rare genetic etiologies of TB in children and young adults: inherited ITK, PD-1, and LY9 deficiencies.These rare genetic defects partially impair IFN-γ production by diverse T cell subsets through distinct mechanisms such as development, exhaustion, and epigenetic imprinting.Thus, the first part of my graduate research demonstrates that even partial impairment of T-cell IFN-γ production can underlie TB in young humans. PD-1 is an inhibitory \"checkpoint\" in T lymphocytes ligated with two known ligands, PD-L1 and PD-L2, to maintain self-tolerance. The PD-1-deficient proband had not only TB but also multi-organ autoimmunity and died of autoimmune pneumonitis at age 11 years. His older brother also had type 1 diabetes and died of pneumonitis of undocumented etiology at age 3 years. Moreover, I had an opportunity to study another two siblings with inherited PD-L1 deficiency, both of whom had early-onset type 1diabetes. Unlike the two PD-1-deficient siblings, neither of the PD-L1-deficient siblings developed any autoimmune phenotypes other than endocrinological autoimmunity. Consistent with their much more severe clinical manifestations, PD-1 deficiency triggered much more severe leukocyte dysregulation than PD-L1 deficiency. The discordant severity in clinical and leukocytic phenotypes in humans with PD-1 and PD-L1 deficiencies suggest that 1) PD-1:PD-L2 interaction can compensate, at least in part, for the absence of PD-1:PD-L1 signal to mitigate unrestrained leukocytic dysregulation in vivo; and that 2) PD-1:PD-L1 signal is nonetheless indispensable in preventing type 1 diabetes in humans. Finally, during these studies, I discovered that PD-1 and PD-L1 contribute to optimal memory B cell development and antibody responses. Surprisingly, PD-1:PD-L1 interactions promote immunoglobulin production in a B-cell-autonomous manner, and a newly established B-cell-specific PD-1 KO mouse line showed a severe contraction of almost all B cell compartments. In fact, the B-cell phenotype was much more severe in B-cell-specific PD-1 KO mice than in whole-body KO mice, suggesting that 1) PD-1 on B cells has a critically indispensable role in the homeostasis of B cells and 2) PD-1 on leukocytes other than B cells (probably T cells) has a unique role in mitigating the disturbance the B-cell compartment. Thus, the second part of my graduate research provides unique insights into the non-redundant roles of PD-1 and PD-L1 in maintaining self-tolerance and functional oral immunity in mice and humans.
","abstract_html":"<p>Tuberculosis (TB), a multi-organ infectious disease caused by virulent mycobacteria, most predominantly M. tuberculosis, remains one of the deadliest infectious diseases in human history. Bacillus Calmette-Guérin (BCG) vaccine, first implemented medically in 1921, has remained the only available vaccine for TB, although its protective effect is moderate. TB occurs in 5-10% of individuals exposed to those pathogens, while 90-95% remain asymptomatic (i.e.,latent infection or spontaneous clearance). This surprisingly large inter-individual variability has long attracted the attention of human geneticists. Classical twin-based genetic studies have demonstrated the presence of a substantial genetic risk of developing TB disease between monozygotic twins. Later, the clinical and genetic characterization of a rare and severe disease caused by weakly virulent and normally harmless mycobacteria, such as the BCG vaccine substrain, now recognized as Mendelian Susceptibility to Mycobacterial Disease (MSMD), demonstrated that IFN-γ is indispensable for antimycobacterial immunity in humans.Moreover, homozygosity for a common missense mutation P1104A in a protein TYK2 was discovered as the first genetic predisposing factor to TB in humans. TYK2 P1104A selectively impairs IL-23-dependent IFN-γ production by lymphocytes.In light of these findings, I hypothesized that a partial impairment of IFN-γ immunity due to known or novel genetic defects underlies vulnerability to TB in humans. I characterized three rare genetic etiologies of TB in children and young adults: inherited ITK, PD-1, and LY9 deficiencies.These rare genetic defects partially impair IFN-γ production by diverse T cell subsets through distinct mechanisms such as development, exhaustion, and epigenetic imprinting.Thus, the first part of my graduate research demonstrates that even partial impairment of T-cell IFN-γ production can underlie TB in young humans. PD-1 is an inhibitory "checkpoint" in T lymphocytes ligated with two known ligands, PD-L1 and PD-L2, to maintain self-tolerance. The PD-1-deficient proband had not only TB but also multi-organ autoimmunity and died of autoimmune pneumonitis at age 11 years. His older brother also had type 1 diabetes and died of pneumonitis of undocumented etiology at age 3 years. Moreover, I had an opportunity to study another two siblings with inherited PD-L1 deficiency, both of whom had early-onset type 1diabetes. Unlike the two PD-1-deficient siblings, neither of the PD-L1-deficient siblings developed any autoimmune phenotypes other than endocrinological autoimmunity. Consistent with their much more severe clinical manifestations, PD-1 deficiency triggered much more severe leukocyte dysregulation than PD-L1 deficiency. The discordant severity in clinical and leukocytic phenotypes in humans with PD-1 and PD-L1 deficiencies suggest that 1) PD-1:PD-L2 interaction can compensate, at least in part, for the absence of PD-1:PD-L1 signal to mitigate unrestrained leukocytic dysregulation in vivo; and that 2) PD-1:PD-L1 signal is nonetheless indispensable in preventing type 1 diabetes in humans. Finally, during these studies, I discovered that PD-1 and PD-L1 contribute to optimal memory B cell development and antibody responses. Surprisingly, PD-1:PD-L1 interactions promote immunoglobulin production in a B-cell-autonomous manner, and a newly established B-cell-specific PD-1 KO mouse line showed a severe contraction of almost all B cell compartments. In fact, the B-cell phenotype was much more severe in B-cell-specific PD-1 KO mice than in whole-body KO mice, suggesting that 1) PD-1 on B cells has a critically indispensable role in the homeostasis of B cells and 2) PD-1 on leukocytes other than B cells (probably T cells) has a unique role in mitigating the disturbance the B-cell compartment. Thus, the second part of my graduate research provides unique insights into the non-redundant roles of PD-1 and PD-L1 in maintaining self-tolerance and functional oral immunity in mice and humans.</p>","abstract_has_math":false,"creators":["Ogishi, Masato"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Jean-Laurent Casanova"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-01-01T08:00:00Z","date_published":"2024-01-01T08:00:00Z","updated_at":"2026-07-24T04:10:53Z","subjects":["tuberculosis","IFN-γ immunity","PD-1 deficiency","PD-L1","LY9","diabetes","Life Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/770","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Jean-Laurent Casanova"]},{"key":"dc:creator","label":"Author","values":["Ogishi, Masato"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2026-03-23T07:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["tuberculosis","IFN-γ immunity","PD-1 deficiency","PD-L1","LY9","diabetes","Life Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/770"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Tuberculosis (TB), a multi-organ infectious disease caused by virulent mycobacteria, most predominantly M. tuberculosis, remains one of the deadliest infectious diseases in human history. Bacillus Calmette-Guérin (BCG) vaccine, first implemented medically in 1921, has remained the only available vaccine for TB, although its protective effect is moderate. TB occurs in 5-10% of individuals exposed to those pathogens, while 90-95% remain asymptomatic (i.e.,latent infection or spontaneous clearance). This surprisingly large inter-individual variability has long attracted the attention of human geneticists. Classical twin-based genetic studies have demonstrated the presence of a substantial genetic risk of developing TB disease between monozygotic twins. Later, the clinical and genetic characterization of a rare and severe disease caused by weakly virulent and normally harmless mycobacteria, such as the BCG vaccine substrain, now recognized as Mendelian Susceptibility to Mycobacterial Disease (MSMD), demonstrated that IFN-γ is indispensable for antimycobacterial immunity in humans.Moreover, homozygosity for a common missense mutation P1104A in a protein TYK2 was discovered as the first genetic predisposing factor to TB in humans. TYK2 P1104A selectively impairs IL-23-dependent IFN-γ production by lymphocytes.In light of these findings, I hypothesized that a partial impairment of IFN-γ immunity due to known or novel genetic defects underlies vulnerability to TB in humans. I characterized three rare genetic etiologies of TB in children and young adults: inherited ITK, PD-1, and LY9 deficiencies.These rare genetic defects partially impair IFN-γ production by diverse T cell subsets through distinct mechanisms such as development, exhaustion, and epigenetic imprinting.Thus, the first part of my graduate research demonstrates that even partial impairment of T-cell IFN-γ production can underlie TB in young humans. PD-1 is an inhibitory \"checkpoint\" in T lymphocytes ligated with two known ligands, PD-L1 and PD-L2, to maintain self-tolerance. The PD-1-deficient proband had not only TB but also multi-organ autoimmunity and died of autoimmune pneumonitis at age 11 years. His older brother also had type 1 diabetes and died of pneumonitis of undocumented etiology at age 3 years. Moreover, I had an opportunity to study another two siblings with inherited PD-L1 deficiency, both of whom had early-onset type 1diabetes. Unlike the two PD-1-deficient siblings, neither of the PD-L1-deficient siblings developed any autoimmune phenotypes other than endocrinological autoimmunity. Consistent with their much more severe clinical manifestations, PD-1 deficiency triggered much more severe leukocyte dysregulation than PD-L1 deficiency. The discordant severity in clinical and leukocytic phenotypes in humans with PD-1 and PD-L1 deficiencies suggest that 1) PD-1:PD-L2 interaction can compensate, at least in part, for the absence of PD-1:PD-L1 signal to mitigate unrestrained leukocytic dysregulation in vivo; and that 2) PD-1:PD-L1 signal is nonetheless indispensable in preventing type 1 diabetes in humans. Finally, during these studies, I discovered that PD-1 and PD-L1 contribute to optimal memory B cell development and antibody responses. Surprisingly, PD-1:PD-L1 interactions promote immunoglobulin production in a B-cell-autonomous manner, and a newly established B-cell-specific PD-1 KO mouse line showed a severe contraction of almost all B cell compartments. In fact, the B-cell phenotype was much more severe in B-cell-specific PD-1 KO mice than in whole-body KO mice, suggesting that 1) PD-1 on B cells has a critically indispensable role in the homeostasis of B cells and 2) PD-1 on leukocytes other than B cells (probably T cells) has a unique role in mitigating the disturbance the B-cell compartment. Thus, the second part of my graduate research provides unique insights into the non-redundant roles of PD-1 and PD-L1 in maintaining self-tolerance and functional oral immunity in mice and humans.
"]},{"key":"dc:title","label":"Title","values":["Human Inborn Errors of Immunity: Tuberculosis, Autoimmunity, and Beyond"]}]}],"canonical_facts":{"dc:contributor":["Jean-Laurent Casanova"],"dc:creator":["Ogishi, Masato"],"dc:date.available":["2026-03-23T07:00:00Z"],"dc:description.abstract":["Tuberculosis (TB), a multi-organ infectious disease caused by virulent mycobacteria, most predominantly M. tuberculosis, remains one of the deadliest infectious diseases in human history. Bacillus Calmette-Guérin (BCG) vaccine, first implemented medically in 1921, has remained the only available vaccine for TB, although its protective effect is moderate. TB occurs in 5-10% of individuals exposed to those pathogens, while 90-95% remain asymptomatic (i.e.,latent infection or spontaneous clearance). This surprisingly large inter-individual variability has long attracted the attention of human geneticists. Classical twin-based genetic studies have demonstrated the presence of a substantial genetic risk of developing TB disease between monozygotic twins. Later, the clinical and genetic characterization of a rare and severe disease caused by weakly virulent and normally harmless mycobacteria, such as the BCG vaccine substrain, now recognized as Mendelian Susceptibility to Mycobacterial Disease (MSMD), demonstrated that IFN-γ is indispensable for antimycobacterial immunity in humans.Moreover, homozygosity for a common missense mutation P1104A in a protein TYK2 was discovered as the first genetic predisposing factor to TB in humans. TYK2 P1104A selectively impairs IL-23-dependent IFN-γ production by lymphocytes.In light of these findings, I hypothesized that a partial impairment of IFN-γ immunity due to known or novel genetic defects underlies vulnerability to TB in humans. I characterized three rare genetic etiologies of TB in children and young adults: inherited ITK, PD-1, and LY9 deficiencies.These rare genetic defects partially impair IFN-γ production by diverse T cell subsets through distinct mechanisms such as development, exhaustion, and epigenetic imprinting.Thus, the first part of my graduate research demonstrates that even partial impairment of T-cell IFN-γ production can underlie TB in young humans. PD-1 is an inhibitory \"checkpoint\" in T lymphocytes ligated with two known ligands, PD-L1 and PD-L2, to maintain self-tolerance. The PD-1-deficient proband had not only TB but also multi-organ autoimmunity and died of autoimmune pneumonitis at age 11 years. His older brother also had type 1 diabetes and died of pneumonitis of undocumented etiology at age 3 years. Moreover, I had an opportunity to study another two siblings with inherited PD-L1 deficiency, both of whom had early-onset type 1diabetes. Unlike the two PD-1-deficient siblings, neither of the PD-L1-deficient siblings developed any autoimmune phenotypes other than endocrinological autoimmunity. Consistent with their much more severe clinical manifestations, PD-1 deficiency triggered much more severe leukocyte dysregulation than PD-L1 deficiency. The discordant severity in clinical and leukocytic phenotypes in humans with PD-1 and PD-L1 deficiencies suggest that 1) PD-1:PD-L2 interaction can compensate, at least in part, for the absence of PD-1:PD-L1 signal to mitigate unrestrained leukocytic dysregulation in vivo; and that 2) PD-1:PD-L1 signal is nonetheless indispensable in preventing type 1 diabetes in humans. Finally, during these studies, I discovered that PD-1 and PD-L1 contribute to optimal memory B cell development and antibody responses. Surprisingly, PD-1:PD-L1 interactions promote immunoglobulin production in a B-cell-autonomous manner, and a newly established B-cell-specific PD-1 KO mouse line showed a severe contraction of almost all B cell compartments. In fact, the B-cell phenotype was much more severe in B-cell-specific PD-1 KO mice than in whole-body KO mice, suggesting that 1) PD-1 on B cells has a critically indispensable role in the homeostasis of B cells and 2) PD-1 on leukocytes other than B cells (probably T cells) has a unique role in mitigating the disturbance the B-cell compartment. Thus, the second part of my graduate research provides unique insights into the non-redundant roles of PD-1 and PD-L1 in maintaining self-tolerance and functional oral immunity in mice and humans.
"],"dc:identifier":["https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/770"],"dc:subject":["tuberculosis","IFN-γ immunity","PD-1 deficiency","PD-L1","LY9","diabetes","Life Sciences"],"dc:title":["Human Inborn Errors of Immunity: Tuberculosis, Autoimmunity, and Beyond"],"thesis:degree_level":["Thesis"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T04:10:53Z"}