Improved Functionality of Exhausted Intrahepatic CXCR5+ CD8+ T Cells Contributes to Chronic Antigen Clearance Upon Immunomodulation

Abstract

Chronic hepatotropic viral infections are characterized by exhausted CD8+ T cells in the presence of cognate antigen in the liver. The impairment of T cell response limits the control of chronic hepatotropic viruses. Immune-modulatory strategies are attractive options to re-invigorate exhausted T cells. However, in hepatotropic viral infections, the knowledge about immune-modulatory effects on the in-situ regulation of exhausted intrahepatic CD8+ T cells is limited. In this study, we elucidated the functional heterogeneity in the pool of exhausted CD8+ T cells in the liver of mice expressing the model antigen Ova in a fraction of hepatocytes. We found a subpopulation of intrahepatic CXCR5+ Ova-specific CD8+ T cells, which are profoundly cytotoxic, exhibiting efficient metabolic functions as well as improved memory recall and self-maintenance. The intrahepatic Ova-specific CXCR5+ CD8+ T cells are possibly tissue resident cells, which may rely largely on OXPHOS and glycolysis to fuel their cellular processes. Importantly, host conditioning with CpG oligonucleotide reinvigorates and promotes exhausted T cell expansion, facilitating complete antigen eradication. The CpG oligonucleotide-mediated reinvigoration may support resident memory T cell formation and the maintenance of CXCR5+ Ova-specific CD8+ T cells in the liver. These findings suggest that CpG oligodinucleotide may preferentially target CXCR5+ CD8+ T cells for expansion to facilitate the revival of exhausted T cells. Thus, therapeutic strategies aiming to expand CXCR5+ CD8+ T cells might provide a novel approach against chronic liver infection.

Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C

“…Suppression of viral replication in the liver correlated with the intrahepatic expression of type I and II IFNs [42]. The importance of the TLR9 signaling as a new target for stimulatory approaches was also emphasized by a recent report demonstrating that host conditioning with the CpG oligonucleotide could restore exhausted intrahepatic CXCR5+ CD8 T cells, via upregulation of co-stimulatory molecules CD80/86 and OX40 on myeloid cells with subsequent increase of CD28-mediated signals on T cells [72].…”

An angel or a devil? Current view on the role of CD8+ T cells in the pathogenesis of myasthenia gravis

“…CXCR5 + CD8 T cells have special phenotypes: for example, 1) cell markers including CD11a, CD11b, CD20, CD25, CD27, CD28, CD38, CD39, CD40, CD43, CD44hi, CD45RA, CD45RO, CD57, CD62L, CD69, CD83, CD94, CD95, CD101, CD103, CXCR5,CD107, CD127, CD137, CD161, CD200, CD244, HLA-DR, 41BBL, Slamf6, and TCRVa7.2 [ 13 , 131 , 145 , 146 , 149 , 151 – 155 , 157 – 160 , 163 – 165 , 167 , 168 , 171 , 174 , 176 – 178 , 180 – 182 , 184 – 190 , 193 – 195 , 197 , 199 , 201 , 204 , 205 , 207 , 211 , 212 , 214 ]; 2) cytokines, chemokines and receptors (CSF-1, IL-2, IL-4, IL-6, IL-7, IL-7R, IL-10, IL-17, IL-18Ra, IL-21, IL-21R, IL-22, IL-23, IL-27, IL-27R, IL-35, IFN-I, IFNAR1, IFN-γ, TGF-β, TNF-α, IL-4R (CD124), CCR2, CCR4, CCR5, CCR6, CCR7, CCR9, CCL5, CXCL1, CXCL5, CXCL10, CXCL12 (SDF-1α), CXCL13, CXCR3, CXCR4, CXCR5, CX3CR1, MIP-1β) [ 144 – 146 , 149 , 151 , 153 , 154 , 157 , 159 – 162 , 165 , 167 , 168 , 170 , 172 – 174 , 176 , 177 , 179 , 181 – 186 , 188 , 190 , 191 , 193 – 197 , 199 , 200 , 205 , 206 , …”

“…Recently, a novel subset of CD8 T cells, CXCR5 + CD8 + T cells, were identified [141][142][143]. CXCR5 + CD8 + T cells have been found to infiltrate the B cell follicle in response to several diseases, including viral infection (simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) , lymphocytic choriomeningitis virus (LCMV) [149,171,172], hepatitis B virus (HBV) [173][174][175][176][177][178][179][180], polycythemia-inducing FV [180], FluA [181,182], HSV [183], DENV2 [184,185], and SARS CoV-2 [186][187][188][189][190], EBV [191]); cancer (colorectal cancer [192][193][194], NCLC [195], hepatocellular carcinoma [175,196], hematologic malignancies [197], pancreatic tumors [198], gastric cancer [199], breast cancer [200], thyroid cancer [201], melanoma [202], and lymphoma [203]); bacterial infection (Escherichia coli, Acinetobacter baumannii, Klebsiella pneumonia, Pseudomonas aeruginosa, and Staphylococcus aureus [204]); parasitic infection (Leishmania mexicana [205]); immunodeficiency disease (CVID <...…”

Role of CXCR5+CD8+ T cells in human hepatitis B virus infection

“…6 Over the past decade, CXCR5 + CD8 + T cells have attracted increasing attention due to their unique ability to provide assistance to B cells in germinal centres and to maintain cytolytic capabilities similar to those of effector CD8 + T cells in infection, autoimmune and tumour microenvironments. [7][8][9] A recent study has shown that CXCR5 + CD8 + T cells produce HBV-specific cytokines and are dramatically associated with HBsAg and HBV-DNA reduction. More importantly, these cells commendably stimulate the activation of B-cells to assist in viral clearance and have the potential to be an efficacious therapeutic target for CHB.…”