The Overlooked Power Players: Why CD8⁺ T Cells Matter in Multiple Sclerosis

For decades, MS has been framed as a CD4-driven autoimmune disease. That view was shaped by CD4-centric EAE models and therapies that modulate helper T cells. Yet an anti-CD4 monoclonal antibody didn’t curb MRI activity in a phase II trial, pushing researchers to revisit other culprits. The review by Salou et al. synthesizes the case for CD8⁺ T cells as major contributors to MS pathology.

The genetic breadcrumb trail
Classic MS genetics highlights HLA-DRB1*15:01 (class II) as the strongest risk allele, implicating CD4 biology. But class I alleles—HLA-A*0301 (risk), HLA-B*0702 (risk), and HLA-A*0201 (protective)—also shape susceptibility. Notably, combinations of class I with DRB115:01 modulate risk further (e.g., DRB115:01 + A0301 increases risk; DRB115:01 + A0201 attenuates it), hinting that CD8 responses can push disease toward or away from pathology depending on HLA context. These patterns are recapitulated in “humanized” mice bearing HLA-A0301 or A*0201.

Take-home: MS genetics isn’t only about helper T cells; class I signals point squarely at CD8⁺ biology.

What do brain lesions actually contain?
Neuropathology consistently finds CD8⁺ T cells outnumber CD4⁺ T cells in MS lesions—including parenchyma and perivascular cuffs—and even in normal-appearing white matter. In some series, CD8⁺ cells exceeded CD4⁺ by orders of magnitude; cortical plaques associated with early progression and cognitive issues also often contain CD8⁺ cells.

Crucially, target cells in MS lesions upregulate MHC-I, enabling recognition by CD8⁺ T cells. Astrocytes, oligodendrocytes, neurons, and axons show increased class I expression with active disease and lesion activity, making them vulnerable to granzyme B/IFN-γ–armed CD8⁺ effectors. Axonal injury correlates with the numbers of CD8⁺ (but not total CD3⁺) cells in biopsies, and live-cell imaging shows neurite transection by antigen-specific CTLs.

Bottom line: The people’s court of histology places CD8⁺ effectors at the scene, with motive (cytotoxic profile) and opportunity (MHC-I on CNS targets).

CSF offers a window into the CNS
When direct brain access is limited, CSF stands in. In early relapsing-remitting MS, effector-memory CD8⁺ T cells are enriched in CSF, many expressing perforin/granzyme and showing heightened migration across blood-brain barrier models. Granzyme A/B levels spike during relapses, underscoring active cytotoxic programs intrathecally.

How do CD8⁺ cells get into the brain?
Multiple gateways are implicated:

α4-integrin: Blocking it in EAE reduces infiltrating CD8⁺ cells and disease severity (paralleling effects on CD4⁺ cells).

MCAM (CD146): Upregulated on a subset of human effector CD8⁺ cells during relapse; MCAM blockade limits their BBB transmigration and lowers EAE scores. Binding partners include laminin-411 on endothelium.

P-glycoprotein (MDR1): Regulates endothelial CCL2 secretion and selectively controls CD8⁺ trafficking; knocking it down diminishes CD8⁺ (but not CD4⁺) entry to brain in EAE. CCL2 transcripts are elevated in MS lesions.

These pathways sketch drug-addressable “access codes” for pathogenic CD8⁺ cells.

The TCR repertoire: few clones, big impact
High-throughput and single-cell studies show oligoclonal CD8⁺ expansions dominate lesions; many of the same clones appear across different brain regions of a given patient—suggesting antigen-driven selection. Importantly, CSF mirrors CNS repertoire more than blood does, making CSF a practical surrogate for tracking pathogenic clones. Blood CD8⁺ expansions also correlate with disease activity by MRI.

What are CD8⁺ T cells “seeing”?
Direct identification of the initiating autoantigens in MS remains hard, clouded by mimicry, epitope spreading, and dual TCRs. Still, several leads emerge:

Higher frequencies of CD8⁺ responses to CNS peptides in relapsing-remitting MS than in controls.

Responses to apoptotic self-epitopes that correlate with disability and appear in CSF.

EBV-reactive CD8⁺ cells enriched intrathecally, raising the possibility that persistent viral antigens (or mimicry) help drive/maintain the CD8⁺ response.

Animal models: CD8⁺ cells can independently drive disease
Several CD8-centric models demonstrate severe, often MS-like CNS autoimmunity:

Adoptive transfer of MOG-specific CD8⁺ T cells produces prolonged, severe EAE in C57BL/6 mice.

MBP-specific CD8⁺ lines elicit rapid, severe disease with lesion patterns closer to human MS than CD4-driven models; disease is blunted by anti-IFN-γ.

Antigen expressed in oligodendrocytes (HA or OVA) + matching CD8⁺ TCRs → inflammation, demyelination, and even spontaneous EAE; blocking the specific MHC-I/peptide interaction prevents disease. These models show that CD8⁺ T cells can initiate and execute CNS pathology, not just amplify it.

IL-17–producing CD8⁺ T cells (Tc17): an inflammatory twist
In active and chronic-active lesions, large fractions of infiltrating T cells (CD4⁺ and CD8⁺) express IL-17, with much lower frequencies in inactive lesions/NAWM. Blood and CSF from MS patients harbor more IL-17–secreting CD8⁺ cells than controls, and in EAE, CD8-derived IL-17 supports Th17 accumulation and disease—linking cytotoxic and Th17 axes.

What about CD161^hi CD8⁺ cells and MAIT cells? CD161 marks human IL-17-competent CD8⁺ subsets; these cells appear in MS lesions and are enriched in blood, but MAIT cells (which constitute much of CD161^hi) are relatively rare in MS CNS tissue, arguing they’re not the main IL-17⁺ CD8⁺ drivers of pathology.

It’s not CD8 versus CD4—it’s a duet
Even as CD8⁺ cells emerge as prime effectors, crosstalk with CD4⁺ T cells matters. CD8⁺ entry may pave the way for broader inflammation; in EAE, dendritic cells can cross-present myelin epitopes, promoting epitope spreading to CD8⁺ T cells and amplifying damage. In lesions, both lineages can produce IL-17, and inflammatory loops likely sustain BBB disruption and antigen availability.

Therapeutic implications (reading between the lines of the data)

The review doesn’t prescribe therapies, but its data suggest testable strategies:

Intercept trafficking: Pathways involving α4-integrin, MCAM, P-glycoprotein/CCL2 are potential levers to limit CD8⁺ entry.

Target effector programs: Molecules linked to granzyme/perforin or Tc17 differentiation (CD161⁺ subsets) could modulate CD8⁺ pathogenicity without blanket immunosuppression.

Track the clones that matter: Because CSF mirrors CNS CD8⁺ repertoires, serial CSF TCR profiling might help monitor intrathecal disease biology and treatment impact.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Salou, M., Nicol, B., Garcia, A., & Laplaud, D. A. (2015). Involvement of CD8+ T cells in multiple sclerosis. Frontiers in immunology, 6, 604.