Transcriptional Repressor Blimp-1 Promotes CD8+ T Cell Terminal Differentiation and Represses the Acquisition of Central Memory T Cell Properties

Abstract

SUMMARY During acute infections, a small population of effector CD8 T cells evades terminal differentiation and survives as long-lived memory T cells. We demonstrate that the transcriptional repressor Blimp-1 enhances the formation of terminally differentiated CD8 T cells during LCMV infection, and Blimp-1 deficiency promotes the acquisition of memory cell properties by effector cells. Blimp-1 expression is preferentially increased in terminally differentiated effector and “effector memory” (TEM) CD8 T cells, and gradually decays after infection as central memory (TCM) cells develop. Blimp-1-/- effector CD8 T cells show some reduction in effector molecule expression, but primarily develop into memory precursor cells that survive better, and more rapidly acquire several TCM attributes, including CD62L and IL-2 expression and enhanced proliferative responses. These results reveal a critical role for Blimp-1 in controlling terminal differentiation and suppressing memory cell developmental potential in effector CD8 T cells during viral infection.

Low-Affinity Memory CD8+ T Cells Mediate Robust Heterologous Immunity

“…Consistent with previous published results (30, 31), a low frequency of N4 OVA primed secondary effectors produced IL-2 (Figure 3E). In contrast, we found that a significantly greater proportion of V4 OVA primed CD45RB lo cells produced IL-2 (Figure 3E).…”

Low-Affinity Memory CD8+ T Cells Mediate Robust Heterologous Immunity

“…Consistent with previous published results (30, 31), a low frequency of N4 OVA primed secondary effectors produced IL-2 (Figure 3E). In contrast, we found that a significantly greater proportion of V4 OVA primed CD45RB lo cells produced IL-2 (Figure 3E).…”

Blimp-1 Rather Than Hobit Drives the Formation of Tissue-Resident Memory CD8+ T Cells in the Lungs

“…We next considered the role of Blimp-1 and its homolog Hobit in the formation of other memory CD8 + T cell subsets. Consistent with previous research demonstrating the repressive role of Blimp-1 in the formation of CD8 + T CM cells ( 24 , 25 ), we observed elevated frequencies of CD44 high CD62L + D b NP366 + cells in the Blimp-1 KO compartment of mixed BM chimeras already during the effector CD8 + T cell response ( Figures 5A,B ). Importantly, Blimp-1 deficiency resulted in a strong increase in the frequency of D b NP366 + CD8 + T CM cells in the circulation, lung and secondary lymphoid organs during the memory phase ( Figures 5C – E ).…”

Epigenetic Modifications Induced by Blimp-1 Regulate CD8+ T Cell Memory Progression during Acute Virus Infection

“…To test whether CD27 expression in CD8 + T cells is regulated by Blimp-1, we examined T cells from LCMV-infected WT and Prdm1 −/− mice. At day 9 post-infection, there was a higher proportion of CD27 + virus-specific CD8 + T cells in the Prdm1 −/− mice compared to controls (Fig3a), consistent with previous reports (Kallies et al, 2009; Rutishauser et al, 2009). This difference was visible at day 7.5 post-infection but increased in magnitude at days 8 and 9 (Fig3b).…”

“…Consistent with previous studies (Rutishauser et al, 2009; Shin et al, 2009), there was a marked increase in both the number and proportion of CD8 + T cells in Prdm1 −/− mice at days 7 and 14 following LCMV-Armstrong infection (Fig1a,b). CD44 hi CD8 + T cells and LCMV-specific CD8 + T cells showed similar increases (Fig1a).…”

“…CD44 hi CD8 + T cells and LCMV-specific CD8 + T cells showed similar increases (Fig1a). Memory-precursor effector CD8 + T cells (MPEC; KLRG1 lo IL-7R hi (Joshi et al, 2007)) were also increased in Prdm1 −/− mice compared to WT at days 7 and 14 post-infection (Fig1c), consistent with previous data (Rutishauser et al, 2009). Deletion of Prdm1 in activated CD8 + T cells from Prdm1 −/− mice was confirmed at day 7 and 14 post LCMV infection (FigS1c).…”

Low-Affinity Memory CD8+ T Cells Mediate Robust Heterologous Immunity

“…Consistent with previous published results (30, 31), a low frequency of N4 OVA primed secondary effectors produced IL-2 (Figure 3E). In contrast, we found that a significantly greater proportion of V4 OVA primed CD45RB lo cells produced IL-2 (Figure 3E).…”

Blimp-1 Rather Than Hobit Drives the Formation of Tissue-Resident Memory CD8+ T Cells in the Lungs

“…We next considered the role of Blimp-1 and its homolog Hobit in the formation of other memory CD8 + T cell subsets. Consistent with previous research demonstrating the repressive role of Blimp-1 in the formation of CD8 + T CM cells ( 24 , 25 ), we observed elevated frequencies of CD44 high CD62L + D b NP366 + cells in the Blimp-1 KO compartment of mixed BM chimeras already during the effector CD8 + T cell response ( Figures 5A,B ). Importantly, Blimp-1 deficiency resulted in a strong increase in the frequency of D b NP366 + CD8 + T CM cells in the circulation, lung and secondary lymphoid organs during the memory phase ( Figures 5C – E ).…”

Epigenetic Modifications Induced by Blimp-1 Regulate CD8+ T Cell Memory Progression during Acute Virus Infection

“…To test whether CD27 expression in CD8 + T cells is regulated by Blimp-1, we examined T cells from LCMV-infected WT and Prdm1 −/− mice. At day 9 post-infection, there was a higher proportion of CD27 + virus-specific CD8 + T cells in the Prdm1 −/− mice compared to controls (Fig3a), consistent with previous reports (Kallies et al, 2009; Rutishauser et al, 2009). This difference was visible at day 7.5 post-infection but increased in magnitude at days 8 and 9 (Fig3b).…”

“…Consistent with previous studies (Rutishauser et al, 2009; Shin et al, 2009), there was a marked increase in both the number and proportion of CD8 + T cells in Prdm1 −/− mice at days 7 and 14 following LCMV-Armstrong infection (Fig1a,b). CD44 hi CD8 + T cells and LCMV-specific CD8 + T cells showed similar increases (Fig1a).…”

“…CD44 hi CD8 + T cells and LCMV-specific CD8 + T cells showed similar increases (Fig1a). Memory-precursor effector CD8 + T cells (MPEC; KLRG1 lo IL-7R hi (Joshi et al, 2007)) were also increased in Prdm1 −/− mice compared to WT at days 7 and 14 post-infection (Fig1c), consistent with previous data (Rutishauser et al, 2009). Deletion of Prdm1 in activated CD8 + T cells from Prdm1 −/− mice was confirmed at day 7 and 14 post LCMV infection (FigS1c).…”

Low-Affinity Memory CD8+ T Cells Mediate Robust Heterologous Immunity

“…Consistent with previous published results (30, 31), a low frequency of N4 OVA primed secondary effectors produced IL-2 (Figure 3E). In contrast, we found that a significantly greater proportion of V4 OVA primed CD45RB lo cells produced IL-2 (Figure 3E).…”

Blimp-1 Rather Than Hobit Drives the Formation of Tissue-Resident Memory CD8+ T Cells in the Lungs

“…We next considered the role of Blimp-1 and its homolog Hobit in the formation of other memory CD8 + T cell subsets. Consistent with previous research demonstrating the repressive role of Blimp-1 in the formation of CD8 + T CM cells ( 24 , 25 ), we observed elevated frequencies of CD44 high CD62L + D b NP366 + cells in the Blimp-1 KO compartment of mixed BM chimeras already during the effector CD8 + T cell response ( Figures 5A,B ). Importantly, Blimp-1 deficiency resulted in a strong increase in the frequency of D b NP366 + CD8 + T CM cells in the circulation, lung and secondary lymphoid organs during the memory phase ( Figures 5C – E ).…”

Epigenetic Modifications Induced by Blimp-1 Regulate CD8+ T Cell Memory Progression during Acute Virus Infection

“…To test whether CD27 expression in CD8 + T cells is regulated by Blimp-1, we examined T cells from LCMV-infected WT and Prdm1 −/− mice. At day 9 post-infection, there was a higher proportion of CD27 + virus-specific CD8 + T cells in the Prdm1 −/− mice compared to controls (Fig3a), consistent with previous reports (Kallies et al, 2009; Rutishauser et al, 2009). This difference was visible at day 7.5 post-infection but increased in magnitude at days 8 and 9 (Fig3b).…”

“…Consistent with previous studies (Rutishauser et al, 2009; Shin et al, 2009), there was a marked increase in both the number and proportion of CD8 + T cells in Prdm1 −/− mice at days 7 and 14 following LCMV-Armstrong infection (Fig1a,b). CD44 hi CD8 + T cells and LCMV-specific CD8 + T cells showed similar increases (Fig1a).…”

“…CD44 hi CD8 + T cells and LCMV-specific CD8 + T cells showed similar increases (Fig1a). Memory-precursor effector CD8 + T cells (MPEC; KLRG1 lo IL-7R hi (Joshi et al, 2007)) were also increased in Prdm1 −/− mice compared to WT at days 7 and 14 post-infection (Fig1c), consistent with previous data (Rutishauser et al, 2009). Deletion of Prdm1 in activated CD8 + T cells from Prdm1 −/− mice was confirmed at day 7 and 14 post LCMV infection (FigS1c).…”